alpha-synuclein and Parkinson-Disease

Parkinson's disease (PD) is the second most debilitating neurodegenerative movement disorder. It is characterized by the presence of fibrillar alpha-synuclein amassed in the neurons, known as Lewy bodies. Certain cellular and molecular events are involved, leading to the degeneration of dopaminergic neurons. However, the origin and implication of such events are still uncertain. Nevertheless, the role of microRNAs (miRNAs) as important biomarkers and therapeutic molecules is unquestionable. The most challenging task by far in PD treatment has been its late diagnosis followed by therapeutics. miRNAs are an emerging hope to meet the need of early diagnosis, thereby promising an improved movement symptom and prolonged life of the patients. The continuous efforts in discovering the role of miRNAs could be made possible by the utilisation of various animal models of PD. These models help us understand insights into the mechanism of the disease. Moreover, miRNAs have been surfaced as therapeutically important molecules with distinct delivery systems enhancing their success rate. This review aims at providing an outline of different miRNAs implicated in either PD-associated gene regulation or involved in therapeutics.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Lewy Bodies; MicroRNAs; Models, Animal; Parkinson Disease

Aberrant aggregation of the misfolded presynaptic protein, α-Synuclein (α-Syn) into Lewy body (LB) and Lewy neuritis (LN) is a major pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Numerous studies have suggested that prefibrillar and fibrillar species of the misfolded α-Syn aggregates are responsible for cell death in PD pathogenesis. However, the precise molecular events during α-Syn aggregation, especially in the early stages, remain elusive. Emerging evidence has demonstrated that liquid-liquid phase separation (LLPS) of α-Syn occurs in the nucleation step of α-Syn aggregation, which offers an alternate non-canonical aggregation pathway in the crowded microenvironment. The liquid-like α-Syn droplets gradually undergo an irreversible liquid-to-solid phase transition into amyloid-like hydrogel entrapping oligomers and fibrils. This new mechanism of α-Syn LLPS and gel formation might represent the molecular basis of cellular toxicity associated with PD. This review aims to demonstrate the recent development of α-Syn LLPS, the underlying mechanism along with the microscopic events of aberrant phase transition. This review further discusses how several intrinsic and extrinsic factors regulate the thermodynamics and kinetics of α-Syn LLPS and co-LLPS with other proteins, which might explain the pathophysiology of α-Syn in various neurodegenerative diseases.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Parkinson Disease; Protein Aggregation, Pathological

α-Synuclein is an abundant protein at the neuronal synapse that has been implicated in Parkinson's disease for over 25 years and characterizes the hallmark pathology of a group of neurodegenerative diseases now known as the synucleinopathies. Physiologically, α-synuclein exists in an equilibrium between a synaptic vesicle membrane-bound α-helical multimer and a cytosolic largely unstructured monomer. Through its membrane-bound state, α-synuclein functions in neurotransmitter release by modulating several steps in the synaptic vesicle cycle, including synaptic vesicle clustering and docking, SNARE complex assembly, and homeostasis of synaptic vesicle pools. These functions have been ascribed to α-synuclein's interactions with the synaptic vesicle SNARE protein VAMP2/synaptobrevin-2, the synaptic vesicle-attached synapsins, and the synaptic vesicle membrane itself. How α-synuclein affects these processes, and whether disease is due to loss-of-function or gain-of-toxic-function of α-synuclein remains unclear. In this review, we provide an in-depth summary of the existing literature, discuss possible reasons for the discrepancies in the field, and propose a working model that reconciles the findings in the literature.

Topics: alpha-Synuclein; Humans; Parkinson Disease; SNARE Proteins; Synapses; Synaptic Vesicles; Vesicle-Associated Membrane Protein 2

The way sporadic Parkinson's disease (PD) is perceived has undergone drastic changes in recent decades. For a long time, PD was considered a brain disease characterized by motor disturbances; however, the identification of several risk factors and the hypothesis that PD has a gastrointestinal onset have shed additional light. Today, after recognition of prodromal non-motor symptoms and the pathological processes driving their evolution, there is a greater understanding of the involvement of other organ systems. For this reason, PD is increasingly seen as a multiorgan and multisystemic pathology that arises from the interaction of susceptible genetic factors with a challenging environment during aging-related decline.

Topics: alpha-Synuclein; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Parkinson Disease; Prodromal Symptoms; Risk Factors

Aggregation of alpha-synuclein (α-syn) is central in Parkinson's disease as well as in other synucleinopathies. Recent evidence suggests that not only intracellular aggregation of α-syn plays an important role for disease pathogenesis but also cell-to-cell propagation of α-syn seems to significantly contribute to pathological changes in synucleinopathies. In this mini-review we summarize current aspects of spreading of α-syn between brain cell types and its role in pathology.

Topics: alpha-Synuclein; Humans; Parkinson Disease; Synucleinopathies

The discovery of mutations in LRRK2 and GBA1 that are linked to Parkinson's disease provided further evidence that autophagy and lysosome pathways are likely implicated in the pathogenic process. Their protein products are important regulators of lysosome function. LRRK2 has kinase-dependent effects on lysosome activity, autophagic efficacy and lysosomal Ca

Topics: alpha-Synuclein; Animals; Glucosylceramidase; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lysosomes; Mutation; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative illness majorly affecting the population between the ages of 55 to 65 years. Progressive dopaminergic neuronal loss and the collective assemblage of misfolded alpha-synuclein in the substantia nigra, remain notable neuro-pathological hallmarks of the disease. Multitudes of mechanistic pathways have been proposed in attempts to unravel the pathogenesis of PD but still, it remains elusive. The convergence of PD pathology is found in organelle dysfunction where mitochondria remain a major contributor. Mitochondrial processes like bioenergetics, mitochondrial dynamics, and mitophagy are under strict regulation by the mitochondrial genome and nuclear genome. These processes aggravate neurodegenerative activities upon alteration through neuroinflammation, oxidative damage, apoptosis, and proteostatic stress. Therefore, the mitochondria have grabbed a central position in the patho-mechanistic exploration of neurodegenerative diseases like PD. The management of PD remains a challenge to physicians to date, due to the variable therapeutic response of patients and the limitation of conventional chemical agents which only offer symptomatic relief with minimal to no disease-modifying effect. This review describes the patho-mechanistic pathways involved in PD not only limited to protein dyshomeostasis and oxidative stress, but explicit attention has been drawn to exploring mechanisms like organelle dysfunction, primarily mitochondria and mitochondrial genome influence, while delineating the newer exploratory targets such as GBA1, GLP, LRRK2, and miRNAs and therapeutic agents targeting them.

Topics: Aged; alpha-Synuclein; Humans; Mitochondria; Oxidative Stress; Parkinson Disease

The accumulation of pathological α-synuclein (α-syn) in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta are the neuropathological features of Parkinson's disease (PD). Recently, the findings of prion-like transmission of α-syn pathology have expanded our understanding of the region-specific distribution of α-syn in PD patients. Accumulating evidence suggests that α-syn aggregates are released from neurons and endocytosed by glial cells, which contributes to the clearance of α-syn. However, the activation of glial cells by α-syn species produces pro-inflammatory factors that decrease the uptake of α-syn aggregates by glial cells and promote the transmission of α-syn between neurons, which promotes the spread of α-syn pathology. In this article, we provide an overview of current knowledge on the role of glia and α-syn pathology in PD pathogenesis, highlighting the relationships between glial responses and the spread of α-syn pathology.

Topics: alpha-Synuclein; Dopaminergic Neurons; Humans; Parkinson Disease; Pars Compacta

Alpha-synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, are characterized by aberrant accumulation of alpha-synuclein and synaptic dysfunction leading to motor and cognitive deficits. Animal models of alpha-synucleinopathy have greatly facilitated the mechanistic understanding of the disease and the development of therapeutics. Various transgenic, alpha-synuclein fibril-injected, and toxin-injected animal models of Parkinson's disease and multiple system atrophy that recapitulate the disease pathology have been developed and widely used. Recent advances in positron emission tomography have allowed the noninvasive visualization of molecular alterations, underpinning behavioral dysfunctions in the brains of animal models and the longitudinal monitoring of treatment effects. Imaging studies in these disease animal models have employed multi-tracer PET designs to reveal dopaminergic deficits together with other molecular alterations. This review focuses on the development of new positron emission tomography tracers and studies of alpha-synuclein, synaptic vesicle glycoprotein 2A neurotransmitter receptor deficits such as dopaminergic receptor, dopaminergic transporter, serotonergic receptor, vesicular monoamine transporter 2, hypometabolism, neuroinflammation, mitochondrial dysfunction and leucine rich repeat kinase 2 in animal models of Parkinson's disease. The outstanding challenges and emerging applications are outlined, such as investigating the gut-brain-axis by using positron emission tomography in animal models, and provide a future outlook.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Multiple System Atrophy; Parkinson Disease; Positron-Emission Tomography

The association between glucocerebrosidase, encoded by GBA, and Parkinson's disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus and, if so, by which mechanism. We first aimed to examine whether variants in the GALC locus and across the genome are associated with galactosylceramidase activity. We performed a genome-wide association study in two independent cohorts from (i) Columbia University; and (ii) the Parkinson's Progression Markers Initiative study, followed by a meta-analysis with a total of 976 PD patients and 478 controls with available data on galactosylceramidase activity. We further analysed the effects of common GALC variants on expression and galactosylceramidase activity using genomic colocalization methods. Mendelian randomization was used to study whether galactosylceramidase activity may be causal in PD. To study the role of rare GALC variants, we analysed sequencing data from 5028 PD patients and 5422 controls. Additionally, we studied the functional impact of GALC knockout on alpha-synuclein accumulation and on glucocerebrosidase activity in neuronal cell models and performed in silico structural analysis of common GALC variants associated with altered galactosylceramidase activity. The top hit in PD genome-wide association study in the GALC locus, rs979812, is associated with increased galactosylceramidase activity (b = 1.2; SE = 0.06; P = 5.10 × 10-95). No other variants outside the GALC locus were associated with galactosylceramidase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased galactosylceramidase expression. Mendelian randomization suggested that increased galactosylceramidase activity may be causally associated with PD (b = 0.025, SE = 0.007, P = 0.0008). We did not find an association between rare GALC variants and PD. GALC knockout using CRISPR-Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced galactosylceramidase levels may be associated with PD. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of galactosylceramidase

Topics: alpha-Synuclein; Galactosylceramidase; Genome-Wide Association Study; Glucosylceramidase; Humans; Hydrolases; Mutation; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the nigrostriatal pathway. Although the exact mechanisms underlying PD are still not completely understood, it is well accepted that α-synuclein plays key pathophysiological roles as the main constituent of the cytoplasmic inclusions known as Lewy bodies. Several post-translational modifications (PTMs), such as the best-known phosphorylation, target α-synuclein and are thus implicated in its physiological and pathological functions. In this review, we present (1) an overview of the pathophysiological roles of α-synuclein, (2) a descriptive analysis of α-synuclein PTMs, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, truncation, and O-GlcNAcylation, as well as (3) a brief summary on α-synuclein PTMs as potential biomarkers for PD. A better understanding of α-synuclein PTMs is of paramount importance for elucidating the mechanisms underlying PD and can thus be expected to improve early detection and monitoring disease progression, as well as identify promising new therapeutic targets.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Neurodegenerative Diseases; Parkinson Disease; Protein Processing, Post-Translational

Parkinson's disease (PD) is a common chronic neurodegenerative disease, and the heat shock proteins (HSPs) are proved to be of great value for PD. In addition, HSPs can maintain protein homeostasis, degrade and inhibit protein aggregation by properly folding and activating intracellular proteins in PD. This study mainly summarizes the important roles of HSPs in PD and explores their feasibility as targets. We introduced the structural and functional characteristics of HSPs and the physiological functions of HSPs in PD. HSPs can protect neurons from damage by degrading aggregates with three mechanisms, including the aggregation and removing α-Synuclein (α-Syn) aggregates, promotion the autophagy of abnormal proteins, and inhibition the apoptosis of degenerated neurons. This study underscores the importance of HSPs as targets in PD and helps to expand new mechanisms in PD treatment strategies.

Topics: alpha-Synuclein; Heat-Shock Proteins; Humans; Neurodegenerative Diseases; Neurons; Parkinson Disease; Protein Aggregates

Parkinson's disease (PD) is the world's second primary neurodegenerative disease, and the diagnosis and treatment of PD have become mainstream research. Over the past decades, several studies have identified potential biomarkers for diagnosing PD. Among them, extracellular vesicles (EVs) can carry specific biomarkers reflecting the physiological and pathological state of the body. Due to the blood-brain barrier (BBB) limitation, peripheral blood is limited in diagnosing neurodegenerative diseases. With the increasing research on EVs, their ability to pass through BBB indicated that peripheral blood could depict disease status like cerebrospinal fluid (CSF). Peripheral blood is a clinically available sample and has recently been widely used by researchers in various studies. In this review, we summarized previous studies on PD diagnosis biomarkers in peripheral blood EVs and evaluated their diagnostic value. Some EV surface markers were also described, which can extract EVs from specific cell origins. In addition, the combination of several biomarkers demonstrated good diagnostic performance in PD diagnosis compared with a single biomarker, suggesting the focus of future research.

Topics: alpha-Synuclein; Biomarkers; Blood-Brain Barrier; Extracellular Vesicles; Humans; Neurodegenerative Diseases; Parkinson Disease

The microbiota-gut-brain axis or simple gut-brain axis (GBA) is a complex and interactive bidirectional communication network linking the gut to the brain. Alterations in the composition of the gut microbiome have been linked to GBA dysfunction, central nervous system (CNS) inflammation, and dopaminergic degeneration, as those occurring in Parkinson's disease (PD). Besides inflammation, the activation of brain microglia is known to play a central role in the damage of dopaminergic neurons. Inflammation is attributed to the toxic effect of aggregated α-synuclein, in the brain of PD patients. It has been suggested that the α-synuclein misfolding might begin in the gut and spread "prion-like", via the vagus nerve into the lower brainstem and ultimately to the midbrain, known as the Braak hypothesis. In this review, we discuss how the microbiota-gut-brain axis and environmental influences interact with the immune system to promote a pro-inflammatory state that is involved in the initiation and progression of misfolded α-synuclein proteins and the beginning of the early non-motor symptoms of PD. Furthermore, we describe a speculative bidirectional model that explains how the enteric glia is involved in the initiation and spreading of inflammation, epithelial barrier disruption, and α-synuclein misfolding, finally reaching the central nervous system and contributing to neuroinflammatory processes involved with the initial non-motor symptoms of PD.

Topics: alpha-Synuclein; Brain; Brain-Gut Axis; Enteric Nervous System; Humans; Inflammation; Neuroglia; Parkinson Disease

Parkinson's disease (PD) is characterized by an abnormal post-translational modifications (PTM) in amino acid sequence and aggregation of alpha-synuclein (α-Syn) protein. It is generally believed that dopamine (DA) metabolite in dopaminergic (DAergic) neurons promotes the aggregation of toxic α-Syn oligomers and protofibrils, whereas DA inhibits the formation of toxic fibers and even degrades the toxic fibers. Therefore, the study on interaction between DA metabolites and α-Syn oligomers is one of the current hot topics in neuroscience, because this effect may have direct relevance to the selective DAergic neuron loss in PD. Several mechanisms have been reported for DA metabolites induced α-Syn oligomers viz. i) The reactive oxygen species (ROS) released during the auto-oxidation or enzymatic oxidation of DA changes the structure of α-Syn by the oxidation of amino acid residue leading to misfolding, ii) The oxidized DA metabolites directly interact with α-Syn through covalent or non-covalent bonding leading to the formation of oligomers, iii) DA interacts with lipid or autophagy related proteins to decreases the degradation efficiency of α-Syn aggregates. However, there is no clear-cut mechanism proposed for the interaction between DA and α-Syn. However, it is believed that the lysine (Lys) side chain of α-Syn sequence is the initial trigger site for the oligomer formation. Herein, we review different chemical mechanism involved during the interaction of Lys side chain of α-Syn with DA metabolites such as dopamine-o-quinone (DAQ), dopamine-chrome (DAC), dopamine-aldehyde (DOPAL) and neuromelanin. This review also provides the promotive effect of divalent Cu

Topics: alpha-Synuclein; Antioxidants; Dopamine; Humans; Parkinson Disease

The protein dyshomeostasis is identified as the hallmark of many age-related neurodegenerative disorders including Parkinson's disease (PD). The diseased brain shows the deposition of Lewy bodies composed of α-synuclein protein aggregates. Functional proteostasis is characterized by the well-coordinated signaling network constituting unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and the autophagy-lysosome pathway (ALP). These networks ensure proper synthesis, folding, confirmation, and degradation of protein i.e., α-synuclein protein in PD. The proper functioning the of intricately woven proteostasis network is quite resilient to sustain under the influence of stressors. The synuclein protein turnover is hugely influenced by the autosomal dominant, recessive, and X-linked mutational changes of a gene involved in UPR, UPS, and ALP. The methylation, acetylation-related epigenetic modifications of DNA and histone proteins along with microRNA-mediated transcriptional changes also lead to extensive proteostasis dysregulation. The result of defective proteostasis is the deposition of many proteins which start appearing in the biofluids and can be identified as potential biomarkers for early diagnosis of PD. The therapeutic intervention targeted at different strata of proteostasis machinery holds great possibilities for delaying the age-related accumulation of pathological hallmarks.

Topics: alpha-Synuclein; Humans; Neurodegenerative Diseases; Parkinson Disease; Proteasome Endopeptidase Complex; Proteostasis; Ubiquitin; Unfolded Protein Response

Parkinson's disease (PD) is an age associated neurological disorder which is specified by cardinal motor symptoms such as tremor, stiffness, bradykinesia, postural instability, and non-motor symptoms. Dopaminergic neurons degradation in substantia nigra region and aggregation of αSyn are the classic signs of molecular defects noticed in PD pathogenesis. The discovery of microRNAs (miRNA) predicted to have a pivotal part in various processes regarding regularizing the cellular functions. Studies on dysregulation of miRNA in PD pathogenesis has recently gained the concern where our review unravels the role of miRNA expression in PD and its necessity in clinical validation for therapeutic development in PD. Here, we discussed how miRNA associated with ageing process in PD through molecular mechanistic approach of miRNAs on sirtuins, tumor necrosis factor-alpha and interleukin-6, dopamine loss, oxidative stress and autophagic dysregulation. Further we have also conferred the expression of miRNAs affected by SNCA gene expression, neuronal differentiation and its therapeutic potential with PD. In conclusion, we suggest more rigorous studies should be conducted on understanding the mechanisms and functions of miRNA in PD which will eventually lead to discovery of novel and promising therapeutics for PD.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Humans; MicroRNAs; Parkinson Disease; Precision Medicine

Interneuronal transfer of pathological α-synuclein species is thought to play an important role in the progressive advancement of Lewy pathology and increasing severity of clinical manifestations in Parkinson's and other diseases commonly referred to as synucleinopathies. Pathophysiological conditions and mechanisms triggering this trans-synaptic spreading bear therefore significant pathogenetic implications but have yet to be fully elucidated. In vivo experimental models support the conclusion that increased expression of intraneuronal α-synuclein can itself induce protein spreading throughout the brain as well as from the brain to peripheral tissues. For example, overexpression of α-synuclein targeted to the rodent dorsal medulla oblongata results in its transfer and accumulation into recipient axons innervating this brain region; through these axons, α-synuclein can then travel caudo-rostrally and reach other brain sites in the pons, midbrain, and forebrain. When protein overexpression is induced in the rodent midbrain, long-distance α-synuclein spreading can be followed over time; spreading-induced α-synuclein accumulation affects lower brain regions, including the dorsal motor nucleus of the vagus, proceeds through efferent axons of the vagus nerve, and is ultimately detected within vagal motor nerve endings in the gastric wall. As discussed in this review, animal models featuring α-synuclein overexpression not only support a relationship between α-synuclein burden and protein spreading but have also provided important clues on conditions/mechanisms capable of promoting interneuronal α-synuclein transfer. Intriguing findings include the relationship between neuronal activity and protein spreading and the role of oxidant stress in trans-synaptic α-synuclein mobility.

Topics: alpha-Synuclein; Animals; Brain; Neurons; Parkinson Disease; Stomach; Synaptic Transmission; Synucleinopathies; Vagus Nerve

Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), are characterized by the misfolding and subsequent aggregation of alpha-synuclein (α-syn) that accumulates in cytoplasmic inclusions bodies in the cells of affected brain regions. Since the seminal report of likely-aggregated α-syn presence within the Lewy bodies by Spillantini et al. in 1997, the keyword "synuclein aggregation" has appeared in over 6000 papers (Source: PubMed October 2022). Studying, observing, describing, and quantifying α-syn aggregation is therefore of paramount importance, whether it happens in tubo, in vitro, in post-mortem samples, or in vivo. The past few years have witnessed tremendous progress in understanding aggregation mechanisms and identifying various polymorphs. In this context of growing complexity, it is of utmost importance to understand what tools we possess, what exact information they provide, and in what context they may be applied. Nonetheless, it is also crucial to rationalize the relevance of the information and the limitations of these methods for gauging the final result. In this review, we present the main techniques that have shaped the current views about α-syn structure and dynamics, with particular emphasis on the recent breakthroughs that may change our understanding of synucleinopathies.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

Parkinson's disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein (aSyn) in the nigrostriatal pathway that is followed by severe neuroinflammatory response. PD etiology is still puzzling; however, the mitocentric view might explain the vast majority of molecular findings not only in the brain, but also at systemic level. While neuronal degeneration is tightly associated with mitochondrial dysfunction, the causal role between aSyn accumulation and mitochondrial dysfunction still requires further investigation. Moreover, mitochondrial dysfunction can elicit an inflammatory response that may be transmitted locally but also in a long range through systemic circulation. Furthermore, mitochondrial-driven innate immune activation may involve the synthesis of antimicrobial peptides, of which aSyn poses as a good candidate. While there is still a need to clarify disease-elicited mechanisms and how aSyn has the ability to modulate mitochondrial and cellular dysfunction, recent studies provide insightful views on mitochondria-inflammation axis in PD etiology.

Topics: alpha-Synuclein; Brain; Humans; Immunity, Innate; Inflammation; Mitochondria; Neurodegenerative Diseases; Parkinson Disease

A key pathological event occurring in Parkinson's disease (PD) is the transneuronal spreading of alpha-synuclein (α-syn). Other hallmarks of PD include neurodegeneration, glial activation, and immune cell infiltration in susceptible brain regions. Although preclinical models can mimic most of the key characteristics of PD, it is crucial to know the biological bases of individual differences between them when choosing one over another, to ensure proper interpretation of the results and to positively influence the outcome of the experiments.. This review provides an overview of current preclinical models actively used to study the interplay between α-syn pathology, neuroinflammation and immune response in PD but also to explore new potential preclinical models or emerging therapeutic strategies intended to fulfill the unmet medical needs in this disease. Lastly, this review also considers the current state of the ongoing clinical trials of new drugs designed to target these processes and delay the initiation or progression of the disease.. Anti-inflammatory and immunomodulatory agents have been demonstrated to be very promising candidates for reducing disease progression; however, more efforts are needed to reduce the enormous gap between these and dopaminergic drugs, which have dominated the therapeutic market for the last sixty years.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Immunity; Neuroinflammatory Diseases; Parkinson Disease

The progressive accumulation of insoluble aggregates of the presynaptic protein alpha-synuclein (α-Syn) is a hallmark of neurodegenerative disorders including Parkinson's disease (PD), Multiple System Atrophy, and Dementia with Lewy Bodies, commonly referred to as synucleinopathies. Despite considerable progress on the structural biology of these aggregates, the molecular mechanisms mediating their cell-to-cell transmission, propagation, and neurotoxicity remain only partially understood. Numerous studies have highlighted the stereotypical spatiotemporal spreading of pathological α-Syn aggregates across different tissues and anatomically connected brain regions over time. Experimental evidence from various cellular and animal models indicate that α-Syn transfer occurs in two defined steps: the release of pathogenic α-Syn species from infected cells, and their uptake via passive or active endocytic pathways. Once α-Syn aggregates have been internalized, little is known about what drives their toxicity or how they interact with the endogenous protein to promote its misfolding and subsequent aggregation. Similarly, unknown genetic factors modulate different cellular responses to the aggregation and accumulation of pathogenic α-Syn species. Here we discuss the current understanding of the molecular phenomena associated with the intercellular spreading of pathogenic α-Syn seeds and summarize the evidence supporting the transmission hypothesis. Understanding the molecular mechanisms involved in α-Syn aggregates transmission is essential to develop novel targeted therapeutics against PD and related synucleinopathies.

Topics: alpha-Synuclein; Animals; Brain; Parkinson Disease; Protein Aggregates; Synucleinopathies

α-Synuclein is a neuronal protein that is enriched in presynaptic terminals. Under physiological conditions, it binds to synaptic vesicle membranes and functions in neurotransmitter release, although the molecular details remain unclear, and it is controversial whether α-synuclein inhibits or facilitates neurotransmitter release. Pathologically, in synucleinopathies including Parkinson's disease (PD), α-synuclein forms aggregates that recruit monomeric α-synuclein and spread throughout the brain, which triggers neuronal dysfunction at molecular, cellular, and organ levels. Here, we present an overview of the effects of α-synuclein on SNARE-complex assembly, neurotransmitter release, and synaptic vesicle pool homeostasis, and discuss how the observed divergent effects of α-synuclein on neurotransmitter release can be reconciled. We also discuss how gain-of-function versus loss-of-function of α-synuclein may contribute to pathogenesis in synucleinopathies.

Topics: alpha-Synuclein; Humans; Neurotransmitter Agents; Parkinson Disease; Synaptic Vesicles; Synucleinopathies

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder characterised by the progressive loss of dopaminergic neurons in the nigrostriatal tract. The identification of disease-modifying therapies is the Holy Grail of PD research, but to date no drug has been approved as such a therapy. A possible reason is the remarkable phenotypic heterogeneity of PD patients, which can generate confusion in the interpretation of results or even mask the efficacy of a therapeutic intervention. This heterogeneity should be taken into account in clinical trials, stratifying patients by their expected response to drugs designed to engage selected molecular targets. In this setting, stratification methods (clinical and genetic) should be supported by biochemical phenotyping of PD patients, in line with the deep phenotyping concept. Collection, from single patients, of a range of biological samples would streamline the generation of these profiles. Several studies have proposed biochemical characterisations of patient cohorts based on analysis of blood, cerebrospinal fluid, urine, stool, saliva and skin biopsy samples, with extracellular vesicles attracting increasing interest as a source of biomarkers. In this review we report and critically discuss major studies that used a biochemical approach to stratify their PD cohorts. The analyte most studied is α-synuclein, while other studies have focused on neurofilament light chain, lysosomal proteins, inflammasome-related proteins, LRRK2 and the urinary proteome. At present, stratification of PD patients, while promising, is still a nascent approach. Deep phenotyping of patients will allow clinical researchers to identify homogeneous subgroups for the investigation of tailored disease-modifying therapies, enhancing the chances of therapeutic success.

Topics: alpha-Synuclein; Biomarkers; Extracellular Vesicles; Humans; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease, and is characterized by accumulation of α-synuclein (α-syn). Neuroinflammation driven by microglia is an important pathological manifestation of PD. α-Syn is a crucial marker of PD, and its accumulation leads to microglia M1-like phenotype polarization, activation of NLRP3 inflammasomes, and impaired autophagy and phagocytosis in microglia. Autophagy of microglia is related to degradation of α-syn and NLRP3 inflammasome blockage to relieve neuroinflammation. Microglial autophagy and phagocytosis of released α-syn or fragments from apoptotic neurons maintain homeostasis in the brain. A variety of PD-related genes such as LRRK2, GBA and DJ-1 also contribute to this stability process.. Further studies are needed to determine how α-syn works in microglia.. A keyword-based search was performed using the PubMed database for published articles.. In this review, we discuss the interaction between microglia and α-syn in PD pathogenesis and the possible mechanism of microglial autophagy and phagocytosis in α-syn clearance and inhibition of neuroinflammation. This may provide a novel insight into treatment of PD.

Topics: alpha-Synuclein; Autophagy; Humans; Inflammasomes; Microglia; Neurodegenerative Diseases; Neuroinflammatory Diseases; NLR Family, Pyrin Domain-Containing 3 Protein; Parkinson Disease; Phagocytosis

Topics: alpha-Synuclein; Autophagy; Gaucher Disease; Glucosylceramidase; Humans; Hydrolases; Lysosomes; Parkinson Disease

Increase evidence from epidemiological studies have shown an inverse association between Parkinson's disease (PD) and lung cancer. PD and lung cancer are both geriatric diseases, where these two diseases are sharing some common genetic determinants. Several PD-associated genes including alpha synuclein (SNCA), PTEN-induced kinase 1 (PINK1), parkin, parkinsonism associated deglycase (DJ-1), leucine-rich repeat kinase 2 (LRRK2), F-box protein 7 (FBXO7) and ubiquitin C-terminal hydrolase L1 (UCHL1) were reported to have altered expressions in lung cancer patients. This indicates that certain PD-associated genes might be important in conferring anticancer effects. This review aims to depict the physiological functions of these genes, and discuss the putative roles of these PD-associated genes in lung cancer. The understanding of the roles of these genes in the lung cancer progression might be important in the identification of new treatment targets for lung cancer. Gene therapy that aims to alter the expressions of these genes could be developed for future anticancer therapy. As a result, studying the roles of these genes in lung cancer may also help to understand their involvements as well as their roles in the pathogenesis of PD.

Topics: Aged; alpha-Synuclein; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lung Neoplasms; Mutation; Parkinson Disease; Protein Kinases; Protein Serine-Threonine Kinases; Ubiquitin-Protein Ligases

Misfolded alpha-synuclein (αSyn) aggregates are a hallmark event in Parkinson's disease (PD) and other synucleinopathies. Recently, αSyn seed amplification assays (αSyn-SAAs) have shown promise as a test for biochemical diagnosis of synucleinopathies. αSyn-SAAs use the intrinsic self-replicative nature of misfolded αSyn aggregates (seeds) to multiply them in vitro. In these assays, αSyn seeds circulating in biological fluids are amplified by a cyclical process that includes aggregate fragmentation into smaller self-propagating seeds, followed by elongation at the expense of recombinant αSyn (rec-αSyn). Amplification of the seeds allows detection by fluorescent dyes specific for amyloids, such as thioflavin T. Several αSyn-SAA reports have been published in the past under the names 'protein misfolding cyclic amplification' (αSyn-PMCA) and 'real-time quaking-induced conversion'. Here, we describe a protocol for αSyn-SAA, originally reported as αSyn-PMCA, which allows detection of αSyn aggregates in cerebrospinal fluid samples from patients affected by PD, dementia with Lewy bodies or multiple-system atrophy (MSA). Moreover, this αSyn-SAA can differentiate αSyn aggregates from patients with PD versus those from patients with MSA, even in retrospective samples from patients with pure autonomic failure who later developed PD or MSA. We also describe modifications to the original protocol introduced to develop an optimized version of the assay. The optimized version shortens the assay length, decreases the amount of rec-αSyn required and reduces the number of inconclusive results. The protocol has a hands-on time of ~2 h per 96-well plate and can be performed by personnel trained to perform basic experiments with specimens of human origin.

Topics: alpha-Synuclein; Humans; Parkinson Disease; Retrospective Studies; Synucleinopathies

Parkinson's disease is a health-threatening neurodegenerative disease of the elderly with clinical manifestations of motor and non-motor deficits such as tremor palsy and loss of smell. Alpha-synuclein (α-Syn) is the pathological basis of PD, it can abnormally aggregate into insoluble forms such as oligomers, fibrils, and plaques, causing degeneration of nigrostriatal dopaminergic neurons in the substantia nigra in the patient's brain and the formation of Lewy bodies (LBs) and Lewy neuritis (LN) inclusions. As a result, achieving α-Syn aggregate detection in the early stages of PD can effectively stop or delay the progression of the disease. In this paper, we provide a brief overview and analysis of the molecular structures and α-Syn in vivo and in vitro detection methods, such as mass spectrometry, antigen-antibody recognition, electrochemical sensors, and imaging techniques, intending to provide more technological support for detecting α-Syn early in the disease and intervening in the progression of Parkinson's disease.

Topics: Aged; alpha-Synuclein; Biomarkers; Humans; Neurodegenerative Diseases; Parkinson Disease; Tremor

We are witnessing a considerable increase in the incidence of Parkinson's disease (PD), which may be due to the general ageing of the population. While there is a plethora of therapeutic strategies for this disease, they still fail to arrest disease progression as they do not target and prevent the neurodegenerative process. The identification of disease-causing mutations allowed researchers to better dissect the underlying causes of this disease, highlighting, for example, the pathogenic role of alpha-synuclein. However, most PD cases are sporadic, which is making it hard to unveil the major causative mechanisms of this disease. In the recent years, epidemiological evidence suggest that type-2 diabetes mellitus (T2DM) individuals have higher risk and worst outcomes of PD, allowing to raise the hypothesis that some dysregulated processes in T2DM may contribute or even trigger the neurodegenerative process in PD. One major consequence of T2DM is the unprogrammed reaction between sugars, increased in T2DM, and proteins, a reaction named glycation. Pre-clinical reports show that alpha-synuclein is a target of glycation, and glycation potentiates its pathogenicity which contributes for the neurodegenerative process. Moreover, it triggers, anticipates, or aggravates several PD-like motor and non-motor complications. A given profile of proteins are differently glycated in diseased conditions, altering the brain proteome and leading to brain dysfunction and neurodegeneration. Herein we coin the term Glycatome as the profile of glycated proteins. In this review we report on the mechanisms underlying the association between T2DM and PD, with particular focus on the impact of protein glycation.

Topics: alpha-Synuclein; Diabetes Mellitus, Type 2; Humans; Maillard Reaction; Parkinson Disease

Development of neuroprotective therapeutics for Parkinson's disease (PD) is facing a lack of translation from pre-clinical to clinical trials. One strategy for improvement is to increase predictive validity of pre-clinical studies by using extensively characterized animal models with a comprehensive set of validated pharmacodynamic readouts. Mice over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter (Thy1-aSyn line 61) reproduce key features of sporadic PD, such as progressive loss of striatal dopamine, alpha-synuclein pathology, deficits in motor and non-motor functions, and elevation of inflammatory markers. Extensive work with this model by multiple laboratories over the past decade further increased confidence in its robustness and validity, especially for analyzing pathomechanisms of alpha-synuclein pathology and down-stream pathways, and for pre-clinical drug testing. Interestingly, while postnatal transgene expression is widespread in central and peripheral neurons, the extent and progression of down-stream pathology differs between brain regions, thereby replicating the characteristic selective vulnerability of neurodegenerative diseases. In-depth characterization of these readouts in conjunction with behavioral deficits has led to more informative endpoints for pre-clinical trials. Each drug tested in Thy1-aSyn line 61 enhances knowledge on how molecular targets, pathology, and functional behavioral readouts are interconnected, thereby further optimizing the platform towards predictive validity for clinical trials. Here, we present the current state of the art using Thy1-aSyn line 61 for drug target discovery, validation, and pre-clinical testing.

Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The hallmarks are the presence of Lewy bodies composed mainly of aggregated α-synuclein and immune activation and inflammation in the brain. The neurotropism of SARS-CoV-2 with induction of cytokine storm and neuroinflammation can contribute to the development of PD. Interestingly, overexpression of α-synuclein in PD patients may limit SARS-CoV-2 neuroinvasion and degeneration of dopaminergic neurons; however, on the other hand, this virus can speed up the α-synuclein aggregation. The review aims to discuss the potential link between COVID-19 and the risk of PD, highlighting the need for further studies to authenticate the potential association. We have also overviewed the influence of SARS-CoV-2 infection on the PD course and management. In this context, we presented the prospects for controlling the COVID-19 pandemic and related PD cases that, beyond global vaccination and novel anti-SARS-CoV-2 agents, may include the development of graphene-based nanoscale platforms offering antiviral and anti-amyloid strategies against PD.

Topics: alpha-Synuclein; COVID-19; Dopaminergic Neurons; Humans; Pandemics; Parkinson Disease; SARS-CoV-2

The SH-SY5Y cell line is a simple and inexpensive

Topics: 1-Methyl-4-phenylpyridinium; alpha-Synuclein; Cell Line; Humans; Neuroblastoma; Parkinson Disease

Parkinson's disease is the second most prevalent neurological disease after Alzheimer's. Primarily, old age males are more affected than females. The aggregates of oligomeric forms of α-synuclein cause the loss of dopaminergic neurons in the substantia nigra pars compacta. Further, it leads to dopamine shortage in the striatum region. According to recent preclinical studies, environmental factors like pesticides, food supplements, pathogens, etc. enter the body through the mouth or nose and ultimately reach the gut. Further, these factors get accumulated in enteric nervous system which leads to misfolding of α-synuclein gene, and aggregation of this gene results in Lewy pathology in the gut and reaches to the brain through the vagus nerve. This evidence showed a strong bidirectional connection between the gut and the brain, which leads to gastrointestinal problems in Parkinson patients. Moreover, several studies reveal that patients with Parkinson experience more gastrointestinal issues in the early stages of the disease, such as constipation, increased motility, gut inflammation, etc. This review article focuses on the transmission of α-synuclein and the mechanisms involved in the link between the gut and the brain in Parkinson's disease. Also, this review explores the various pathways involved in Parkinson and current therapeutic approaches for the improvement of Parkinson's disease.

Topics: alpha-Synuclein; Brain; Brain-Gut Axis; Dopaminergic Neurons; Female; Humans; Male; Parkinson Disease; Vagus Nerve

Parkinson's disease (PD) is the most common neurological movement disorder characterized by the selective and irreversible loss of dopaminergic neurons in substantia nigra pars compacta resulting in dopamine deficiency in the striatum. While most cases are sporadic or environmental, about 10% of patients have a positive family history with a genetic cause. The misfolding and aggregation of α-synuclein (α-syn) as a casual factor in the pathogenesis of PD has been supported by a great deal of literature. Extensive studies of mechanisms underpinning degeneration of the dopaminergic neurons induced by α-syn dysfunction suggest a complex process that involves multiple pathways, including mitochondrial dysfunction and increased oxidative stress, impaired calcium homeostasis through membrane permeabilization, synaptic dysfunction, impairment of quality control systems, disruption of microtubule dynamics and axonal transport, endoplasmic reticulum/Golgi dysfunction, nucleus malfunction, and microglia activation leading to neuroinflammation. Among them mitochondrial dysfunction has been considered as the most primary target of α-syn-induced toxicity, leading to neuronal cell death in both sporadic and familial forms of PD. Despite reviewing many aspects of PD pathogenesis related to mitochondrial dysfunction, a systemic study on how α-syn malfunction/aggregation damages mitochondrial functionality and leads to neurodegeneration is missing in the literature. In this review, we give a detailed molecular overview of the proposed mechanisms by which α-syn, directly or indirectly, contributes to mitochondrial dysfunction. This may provide valuable insights for development of new therapeutic approaches in relation to PD. Antioxidant-based therapy as a potential strategy to protect mitochondria against oxidative damage, its challenges, and recent developments in the field are discussed.

Topics: alpha-Synuclein; Antioxidants; Dopaminergic Neurons; Humans; Mitochondria; Oxidative Stress; Parkinson Disease

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. There are no available therapeutics that slow or halt the progressive loss of dopamine-producing neurons, which underlies the primary clinical symptoms. Currently approved PD drugs can provide symptomatic relief by increasing brain dopamine content or activity; however, the alleviation is temporary, and the effectiveness diminishes with the inevitable progression of neurodegeneration. Discovery and development of disease-modifying neuroprotective therapies has been hampered by insufficient understanding of the root cause of PD-related neurodegeneration. The etiology of PD involves a combination of genetic and environmental factors. Although a single cause has yet to emerge, genetic, cell biological and neuropathological evidence implicates mitochondrial dysfunction and protein aggregation. Postmortem PD brains show pathognomonic Lewy body intraneuronal inclusions composed of aggregated α-synuclein, indicative of failure to degrade misfolded protein. Mutations in the genes that code for α-synuclein, as well as the E3 ubiquitin ligase Parkin, cause rare inherited forms of PD. While many ubiquitin ligases label proteins with ubiquitin chains to mark proteins for degradation by the proteasome, Parkin has been shown to mark dysfunctional mitochondria for degradation by mitophagy. The ubiquitin proteasome system participates in several aspects of the cell's response to mitochondrial damage, affording numerous therapeutic opportunities to augment mitophagy and potentially stop PD progression. This review examines the role and therapeutic potential of such UPS modulators, exemplified by both ubiquitinating and deubiquitinating enzymes.

Topics: alpha-Synuclein; Dopamine; Humans; Neurodegenerative Diseases; Parkinson Disease; Proteasome Endopeptidase Complex; Ubiquitin; Ubiquitin-Protein Ligases

Parkinson's disease (PD) is a common neurodegenerative disorder caused by the loss of dopamine neurons in the substantia nigra and the formation of Lewy bodies, which are mainly composed of alpha-synuclein fibrils. Alpha-synuclein plays a vital role in the neuroinflammation mediated by the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in PD. A better understanding of the NLRP3 inflammasome-mediated neuroinflammation and the related mitochondrial impairment during PD progression may facilitate the development of promising therapies for PD. This review focuses on the molecular mechanisms underlying NLRP3 inflammasome activation, comprising priming and protein complex assembly, as well as the role of mitochondrial impairment and its subsequent inflammatory effects on the progression of neurodegeneration in PD. In addition, the therapeutic strategies targeting the NLRP3 inflammasome for PD treatment are discussed, including the inhibitors of NLRP3 inflammatory pathways, mitochondria-focused treatments, microRNAs, and other therapeutic compounds.

Topics: alpha-Synuclein; Humans; Inflammasomes; Mitochondria; Neuroinflammatory Diseases; NLR Family, Pyrin Domain-Containing 3 Protein; Parkinson Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects elderly people and constitutes a major source of disability worldwide. Notably, the neuropathological hallmarks of PD include nigrostriatal loss and the formation of intracellular inclusion bodies containing misfolded α-synuclein protein aggregates. Cardinal motor symptoms, which include tremor, rigidity and bradykinesia, can effectively be managed with dopaminergic therapy for years following symptom onset. Nonetheless, patients ultimately develop symptoms that no longer fully respond to dopaminergic treatment. Attempts to discover disease-modifying agents have increasingly been supported by translational molecular imaging concepts, targeting the most prominent pathological hallmark of PD, α-synuclein accumulation, as well as other molecular pathways that contribute to the pathophysiology of PD. Indeed, molecular imaging modalities such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can be leveraged to study parkinsonism not only in animal models but also in living patients. For instance, mitochondrial dysfunction can be assessed with probes that target the mitochondrial complex I (MC-I), while nigrostriatal degeneration is typically evaluated with probes designed to non-invasively quantify dopaminergic nerve loss. In addition to dopaminergic imaging, serotonin transporter and N-methyl-D-aspartate (NMDA) receptor probes are increasingly used as research tools to better understand the complexity of neurotransmitter dysregulation in PD. Non-invasive quantification of neuroinflammatory processes is mainly conducted by targeting the translocator protein 18 kDa (TSPO) on activated microglia using established imaging agents. Despite the overwhelming involvement of the brain and brainstem, the pathophysiology of PD is not restricted to the central nervous system (CNS). In fact, PD also affects various peripheral organs such as the heart and gastrointestinal tract - primarily via autonomic dysfunction. As such, research into peripheral biomarkers has taken advantage of cardiac autonomic denervation in PD, allowing the differential diagnosis between PD and multiple system atrophy with probes that visualize sympathetic nerve terminals in the myocardium. Further, α-synuclein has recently gained attention as a potential peripheral biomarker in PD. This review discusses breakthrough discoveries that have led to the contemporary mol

Topics: alpha-Synuclein; Animals; Dopamine; Drug Development; Molecular Imaging; Parkinson Disease; Parkinsonian Disorders

The neurovascular unit (NVU) is composed of vascular cells, glial cells, and neurons. As a fundamental functional module in the central nervous system, the NVU maintains homeostasis in the microenvironment and the integrity of the blood-brain barrier. Disruption of the NVU and interactions among its components are involved in the pathophysiology of synucleinopathies, which are characterized by the pathological accumulation of α-synuclein. Neuroinflammation contributes to the pathophysiology of synucleinopathies, including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. This review aims to summarize the neuroinflammatory response of glial cells and vascular cells in the NVU. We also review neuroinflammation in the context of the cross-talk between glial cells and vascular cells, between glial cells and pericytes, and between microglia and astroglia. Last, we discuss how α-synuclein affects neuroinflammation and how neuroinflammation influences the aggregation and spread of α-synuclein and analyze different properties of α-synuclein in synucleinopathies.

Topics: alpha-Synuclein; Humans; Neuroinflammatory Diseases; Neurons; Parkinson Disease; Synucleinopathies

Alpha-synuclein is a neuronal protein with unclear function but is associated with the pathogenesis of Parkinson's disease and other synucleinopathies. In this review, we discuss the emerging functional role of alpha-synuclein in support of the unique immune responses in the nervous system. Recent data now show that alpha-synuclein functions to support interferon signaling within neurons and is released from neurons to support chemoattraction and activation of local glial cells and infiltrating immune cells. Inflammatory activation and interferon signaling also induce post-translational modifications of alpha-synuclein that are commonly associated with Parkinson's disease pathogenesis. Taken together, emerging data implicate complex interactions between alpha-synuclein and host immune responses that may contribute to the pathogenesis of Parkinson's disease. Additional study of the function of alpha-synuclein in the brain's immune response may provide disease-modifying therapeutic targets for Parkinson's disease in the future.

Topics: alpha-Synuclein; Humans; Neurons; Parkinson Disease

The synucleinopathies, which include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are a class of human neurodegenerative disorders unified by the presence of α-synuclein aggregates in the brain. Considerable clinical and pathological heterogeneity exists within and among the individual synucleinopathies. A potential explanation for this variability is the existence of distinct conformational strains of α-synuclein aggregates that cause different disease manifestations. Like prion strains, α-synuclein strains can be delineated based on their structural architecture, with structural differences among α-synuclein aggregates leading to unique biochemical attributes and neuropathological properties in humans and animal models. Bolstered by recent high-resolution structural data from patient brain-derived material, it has now been firmly established that there are conformational differences among α-synuclein aggregates from different human synucleinopathies. Moreover, recombinant α-synuclein can be polymerized into several structurally distinct aggregates that exhibit unique pathological properties. In this review, we outline the evidence supporting the existence of α-synuclein strains and highlight how they can act as drivers of phenotypic heterogeneity in the human synucleinopathies.

Topics: alpha-Synuclein; Animals; Brain; Humans; Multiple System Atrophy; Parkinson Disease; Protein Conformation; Synucleinopathies

The clinicopathologic model that defines neurodegenerative disorders has remained unchanged for over a century. According to it, clinical manifestations are defined and explained by a given pathology, that is, by the burden and distribution of selected proteins aggregated into insoluble amyloids. There are two logical consequences from this model: (1) a measurement of the disease-defining pathology represents a biomarker of that disease in everyone affected, and (2) the targeted elimination of that pathology should end that disease. But success in disease modification guided by this model has remained elusive. New technologies to probe living biology have been used to validate rather than question the clinicopathologic model, despite three important observations: (1) a disease-defining pathology in isolation (without other pathologies) is an exceptional autopsy finding; (2) many genetic and molecular pathways converge on the same pathology; (3) the presence of pathology without neurological disease is more common than expected by chance. We here discuss the rationale for abandoning the clinicopathologic model, review the competing biological model of neurodegeneration, and propose developmental pathways for biomarker development and disease-modifying efforts. Further, in justifying future disease-modifying trials testing putative neuroprotective molecules, a key inclusion criterion must be the deployment of a bioassay of the mechanism corrected by the therapy of interest. No improvements in trial design or execution can overcome the fundamental deficit created by testing experimental therapies in clinically defined recipients unselected for their biologically suitability. Biological subtyping is the key developmental milestone needed to launch precision medicine for patients living with neurodegenerative disorders.

Topics: alpha-Synuclein; Biomarkers; Humans; Neurodegenerative Diseases; Parkinson Disease; Precision Medicine

Parkinson's disease is a progressive neurodegenerative disorder that is associated with motor and nonmotor symptoms. Accumulation of misfolded α-synuclein is considered a key pathological feature during disease initiation and progression. While clearly deemed a synucleinopathy, the development of amyloid-β plaques, tau-containing neurofibrillary tangles, and even TDP-43 protein inclusions occur within the nigrostriatal system and in other brain regions. In addition, inflammatory responses, manifested by glial reactivity, T-cell infiltration, and increased expression of inflammatory cytokines, plus other toxic mediators derived from activated glial cells, are currently recognized as prominent drivers of Parkinson's disease pathology. However, copathologies have increasingly been recognized as the rule (>90%) and not the exception, with Parkinson's disease cases on average exhibiting three different copathologies. While microinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy may have an impact on disease progression, α-synuclein, amyloid-β, and TDP-43 pathology do not seem to contribute to progression.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; DNA-Binding Proteins; Humans; Neurofibrillary Tangles; Parkinson Disease; tau Proteins

With a current lack of disease-modifying treatments, an initiative toward implementing a precision medicine approach for treating Parkinson's disease (PD) has emerged. However, challenges remain in how to define and apply precision medicine in PD. To accomplish the goal of optimally targeted and timed treatment for each patient, preclinical research in a diverse population of rodent models will continue to be an essential part of the translational path to identify novel biomarkers for patient diagnosis and subgrouping, understand PD disease mechanisms, identify new therapeutic targets, and screen therapeutics prior to clinical testing. This review highlights the most common rodent models of PD and discusses how these models can contribute to defining and implementing precision medicine for the treatment of PD.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Humans; Parkinson Disease; Precision Medicine; Rodentia

Beta-glucocerebrosidase is a lysosomal hydrolase, encoded by GBA1 that represents the most common risk gene associated with Parkinson's disease (PD) and Lewy Body Dementia. Glucocerebrosidase dysfunction has been also observed in the absence of GBA1 mutations across different genetic and sporadic forms of PD and related disorders, suggesting a broader role of glucocerebrosidase in neurodegeneration. In this review, we highlight recent advances in mechanistic characterization of glucocerebrosidase function as the foundation for development of novel therapeutics targeting glucocerebrosidase in PD and related disorders.

Topics: alpha-Synuclein; Glucosylceramidase; Humans; Lysosomes; Mutation; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disorder that has been associated with mitochondrial dysfunction, oxidative stress, and defects in mitophagy as well as α-synuclein-positive inclusions, termed Lewy bodies (LBs), which are a common pathological hallmark in PD. Mitophagy is a process that maintains cellular health by eliminating dysfunctional mitochondria, and it is triggered by ubiquitination of mitochondrial-associated proteins-e.g., through the PINK1/Parkin pathway-which results in engulfment by the autophagosome and degradation in lysosomes. Deubiquitinating enzymes (DUBs) can regulate this process at several levels by deubiquitinating mitochondrial substrates and other targets in the mitophagic pathway, such as Parkin. Moreover, DUBs can affect α-synuclein aggregation through regulation of degradative pathways, deubiquitination of α-synuclein itself, and/or via co-localization with α-synuclein in inclusions. DUBs with a known association to PD are described in this paper, along with their function. Of interest, DUBs could be useful as novel therapeutic targets against PD through regulation of PD-associated defects.

Topics: alpha-Synuclein; Deubiquitinating Enzymes; Humans; Parkinson Disease; Ubiquitin-Protein Ligases; Ubiquitination

Although the discovery of the critical role of α-synuclein (α-syn) in the pathogenesis of Parkinson's disease (PD) is now twenty-five years old, it still represents a milestone in PD research. Abnormal forms of α-syn trigger selective and progressive neuronal death through mitochondrial impairment, lysosomal dysfunction, and alteration of calcium homeostasis not only in PD but also in other α-syn-related neurodegenerative disorders such as dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, and REM sleep behavior disorder. Furthermore, α-syn-dependent early synaptic and plastic alterations and the underlying mechanisms preceding overt neurodegeneration have attracted great interest. In particular, the presence of early inflammation in experimental models and PD patients, occurring before deposition and spreading of α-syn, suggests a mechanistic link between inflammation and synaptic dysfunction. The knowledge of these early mechanisms is of seminal importance to support the research on reliable biomarkers to precociously identify the disease and possible disease-modifying therapies targeting α-syn. In this review, we will discuss these critical issues, providing a state of the art of the role of this protein in early PD and other synucleinopathies.

Topics: alpha-Synuclein; Humans; Inflammation; Lewy Bodies; Parkinson Disease; Synucleinopathies

Dysfunction of the serotonergic system represents an important feature in synucleinopathies like Parkinson disease (PD), dementia with Lewy bodies (DLB) and Multiple system atrophy (MSA). Serotonergic fibers from the raphe nuclei (RN) extend broadly throughout the central nervous system, innervating several brain areas affected in synucleinopathies. Alterations of the serotonergic system are associated with non-motor symptoms or motor complications in PD as well as with autonomic features of MSA. Postmortem studies, data from transgenic animal models and imaging techniques greatly contributed to the understanding of this serotonergic pathophysiology in the past, even leading to preclinical and clinical candidate drug tests targeting different parts of the serotonergic system. In this article, we review most recent work extending the knowledge of the serotonergic system and highlighting its relevance for the pathophysiology of synucleinopathies.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Serotonin; Synucleinopathies

Alpha-synuclein inclusions are the distinctive trait of brain areas affected by neurodegeneration in Parkinson's disease (PD). Nevertheless, PD is now considered as a multisystemic disorder, since alpha-synuclein pathology has been described also outside the central nervous system. In this regard, the early, non-motor autonomic symptoms point out an important role for the peripheral nervous system during disease progression. On this basis, we propose a review of the alpha-synuclein-related pathological processes observed at peripheral level in PD, starting from molecular mechanisms, through cellular processes to systemic modifications. We discuss their relevance in the etiopathogenesis of the disease, suggesting they are concurrent players in the development of PD, and that the periphery is an easily-accessible window to look at what is occurring in the central nervous system.

Topics: alpha-Synuclein; Brain; Central Nervous System; Disease Progression; Humans; Parkinson Disease

Parkinson's disease (PD) is a multifarious neurodegenerative disease. Its pathology is characterized by a prominent early death of dopaminergic neurons in the pars compacta of the substantia nigra and the presence of Lewy bodies with aggregated α-synuclein. Although the α-synuclein pathological aggregation and propagation, induced by several factors, is considered one of the most relevant hypotheses, PD pathogenesis is still a matter of debate. Indeed, environmental factors and genetic predisposition play an important role in PD. Mutations associated with a high risk for PD, usually called monogenic PD, underlie 5% to 10% of all PD cases. However, this percentage tends to increase over time because of the continuous identification of new genes associated with PD. The identification of genetic variants that can cause or increase the risk of PD has also given researchers the possibility to explore new personalized therapies. In this narrative review, we discuss the recent advances in the treatment of genetic forms of PD, focusing on different pathophysiologic aspects and ongoing clinical trials.

Topics: alpha-Synuclein; Humans; Neurodegenerative Diseases; Parkinson Disease; Substantia Nigra; Synucleinopathies

Parkinson's disease (PD) is a neurodegenerative condition characterized by the progressive deterioration of dopaminergic neurons in the central and peripheral autonomous system and the intraneuronal cytoplasmic accumulation of misfolded α-synuclein. The clinical features are the classic triad of tremor, rigidity, and bradykinesia and a set of non-motor symptoms, including visual deficits. The latter seems to arise years before the onset of motor symptoms and reflects the course of brain disease. The retina, by virtue of its similarity to brain tissue, is an excellent site for the analysis of the known histopathological changes of PD that occur in the brain. Numerous studies conducted on animal and human models of PD have shown the presence of α-synuclein in retinal tissue. Spectral-domain optical coherence tomography (SD-OCT) could be a technique that enables the study of these retinal alterations in vivo. The objective of this review is to describe recent evidence on the accumulation of native or modified α-synuclein in the human retina of patients with PD and its effects on the retinal tissue evaluated through SD-OCT.

Topics: alpha-Synuclein; Animals; Brain; Humans; Parkinson Disease; Retina; Tremor

α-Synucleinopathies, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, are a class of neurodegenerative diseases exhibiting intracellular inclusions of misfolded α-synuclein (αSyn), referred to as Lewy bodies or oligodendroglial cytoplasmic inclusions (Papp-Lantos bodies). Even though the specific cellular distribution of aggregated αSyn differs in PD and DLB patients, both groups show a significant pathological overlap, raising the discussion of whether PD and DLB are the same or different diseases. Besides clinical investigation, we will focus in addition on methodologies, such as protein seeding assays (real-time quaking-induced conversion), to discriminate between different types of α-synucleinopathies. This approach relies on the seeding conversion properties of misfolded αSyn, supporting the hypothesis that different conformers of misfolded αSyn may occur in different types of α-synucleinopathies. Understanding the pathological processes influencing the disease progression and phenotype, provoked by different αSyn conformers, will be important for a personalized medical treatment in future.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

The identification of disease-causing mutations or strong risk factors for Parkinson's disease in genes encoding proteins such as α-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2), or glucocerebrosidase (GBA1) has led to a better understanding of the different components of disease pathogenesis. Many gene and mutation-specific targeted disease-modifying treatments are under development and several studies are under way. It is, therefore, important to raise awareness among patients and their families and to offer genetic testing, at least to those patients who are considering to participate in innovative trials.

Topics: alpha-Synuclein; Genetic Testing; Glucosylceramidase; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease

The formation of aggregates due to protein misfolding is encountered in various neurodegenerative diseases. α-Synuclein (α-Syn) aggregation is linked to Parkinson's disease (PD). It is one of the most prevalent neurodegenerative disorders after Alzheimer's disease. Aggregation of α-Syn is associated with Lewy body formation and degeneration of the dopaminergic neurons in the brain. These are the pathological hallmarks of PD progression. α-Syn aggregates in a multi-step process. The native unstructured α-Syn monomers combine to form oligomers, followed by amyloid fibrils, and finally Lewy bodies. Recent evidence suggests that α-Syn oligomerization and fibrils formation play major roles in PD development. α-Syn oligomeric species is the main contributor to neurotoxicity. Therefore, the detection of α-Syn oligomers and fibrils has drawn significant attention for potential diagnostic and therapeutic development. In this regard, the fluorescence strategy has become the most popular approach for following the protein aggregation process. Thioflavin T (ThT) is the most frequently used probe for monitoring amyloid kinetics. Unfortunately, it suffers from several significant drawbacks including the inability to detect neurotoxic oligomers. Researchers developed several small molecule-based advanced fluorescent probes compared to ThT for the detection/monitoring of α-Syn aggregates states. These are summarized here.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Fluorescent Dyes; Humans; Parkinson Disease; Protein Aggregates; Protein Aggregation, Pathological

Dopamine (DA) is a key neurotransmitter in the basal ganglia, implicated in the control of movement and motivation. Alteration of DA levels is central in Parkinson's disease (PD), a common neurodegenerative disorder characterized by motor and non-motor manifestations and deposition of alpha-synuclein (α-syn) aggregates. Previous studies have hypothesized a link between PD and viral infections. Indeed, different cases of parkinsonism have been reported following COVID-19. However, whether SARS-CoV-2 may trigger a neurodegenerative process is still a matter of debate. Interestingly, evidence of brain inflammation has been described in postmortem samples of patients infected by SARS-CoV-2, which suggests immune-mediated mechanisms triggering the neurological sequelae. In this review, we discuss the role of proinflammatory molecules such as cytokines, chemokines, and oxygen reactive species in modulating DA homeostasis. Moreover, we review the existing literature on the possible mechanistic interplay between SARS-CoV-2-mediated neuroinflammation and nigrostriatal DAergic impairment, and the cross-talk with aberrant α-syn metabolism.

Topics: alpha-Synuclein; COVID-19; Dopamine; Humans; Neuroinflammatory Diseases; Parkinson Disease; SARS-CoV-2

Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson's disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.

Topics: alpha-Synuclein; Humans; Inflammation; Neurodegenerative Diseases; Parkinson Disease; Synucleinopathies

The accumulation of aggregated α-synuclein in susceptible neurons in the brain, together with robust activation of nearby myeloid cells, are pathological hallmarks of Parkinson's disease (PD). While microglia represent the dominant type of myeloid cell in the brain, recent genetic and whole-transcriptomic studies have implicated another type of myeloid cell, bone-marrow derived monocytes, in disease risk and progression. Monocytes in circulation harbor high concentrations of the PD-linked enzyme leucine-rich repeat kinase 2 (LRRK2) and respond to both intracellular and extracellular aggregated α-synuclein with a variety of strong pro-inflammatory responses. This review highlights recent findings from studies that functionally characterize monocytes in PD patients, monocytes that infiltrate into cerebrospinal fluid, and emerging analyses of whole myeloid cell populations in the PD-affected brain that include monocyte populations. Central controversies discussed include the relative contribution of monocytes acting in the periphery from those that might engraft in the brain to modify disease risk and progression. We conclude that further investigation into monocyte pathways and responses in PD, especially the discovery of additional markers, transcriptomic signatures, and functional classifications, that better distinguish monocyte lineages and responses in the brain from other types of myeloid cells may reveal points for therapeutic intervention, as well as a better understanding of ongoing inflammation associated with PD.

Topics: alpha-Synuclein; Brain; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Monocytes; Mutation; Parkinson Disease

Cognitive impairment occurs in most individuals with Parkinson's disease (PD), exacting a high toll on patients, their caregivers, and the healthcare system. In this review, we begin by summarizing the current clinical landscape surrounding cognition in PD. We then discuss how cognitive impairment and dementia may develop in PD based on the spread of the pathological protein alpha-synuclein (aSyn) from neurons in brainstem regions to those in the cortical regions of the brain responsible for higher cognitive functions, as first proposed in the Braak hypothesis. We appraise the Braak hypothesis from molecular (conformations of aSyn), cell biological (cell-to-cell spread of pathological aSyn), and organ-level (region-to-region spread of aSyn pathology at the whole brain level) viewpoints. Finally, we argue that individual host factors may be the most poorly understood aspect of this pathological process, accounting for substantial heterogeneity in the pattern and pace of cognitive decline in PD.

Topics: alpha-Synuclein; Brain; Cognition; Humans; Parkinson Disease; Synucleinopathies

Alpha-synuclein (αS) is a small, presynaptic neuronal protein encoded by the

Topics: alpha-Synuclein; DNA Methylation; Epigenesis, Genetic; Gene Expression; Humans; Parkinson Disease

Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are termed synucleinopathies, disorders that are characterized by the intracellular aggregation of the protein ɑ-synuclein. The cellular tropism of synuclein pathology in these syndromes is notably distinct since in the Lewy disorders, PD and DLB, ɑSyn forms aggregates in neurons whereas in MSA ɑSyn forms aggregates in oligodendrocytes. Studies examining ɑSyn pathology in experimental models and in human brain have now identified fibrillar ɑSyn with unique but distinct molecular signatures, suggesting that the structure of these ɑSyn fibrils might be closely tied to their cellular ontogeny. In contrast to the native structural heterogeneity of ɑSyn in vitro, the conformational landscape of fibrillar ɑSyn in human brain and in vivo transmission models appears to be remarkably uniform. Here, we review the studies by which we propose a hypothesis that the cellular host environment might be in part responsible for how ɑSyn filaments assemble into phenotype-specific strains. We postulate that the maturation of ɑSyn strains develops as a function of their in vivo transmission routes and cell-specific risk factors. The impact of the cellular environment on the structural diversity of ɑSyn might have important implications for the design of preclinical studies and their use for the development of ɑSyn-based biomarkers and therapeutic strategies. By combining phenotype-specific fibrils and relevant synucleinopathy transmission models, preclinical models might more closely reflect unique disease phenotypes.

Topics: alpha-Synuclein; Humans; Multiple System Atrophy; Neurons; Parkinson Disease; Synucleinopathies

The ultimate origin of Lewy body disorders, including Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), is still incompletely understood. Although a large number of pathogenic mechanisms have been implicated, accumulating evidence support that aggregation and neuron-to-neuron propagation of alpha-synuclein may be the core feature of these disorders. The synuclein, origin, and connectome (SOC) disease model of Lewy body disorders was recently introduced. This model is based on the hypothesis that in the majority of patients, the first alpha-synuclein pathology arises in single location and spreads from there. The most common origin sites are the enteric nervous system and the olfactory system. The SOC model predicts that gut-first pathology leads to a clinical body-first subtype characterized by prodromal autonomic symptoms and REM sleep behavior disorder. In contrast, olfactory-first pathology leads to a brain-first subtype with fewer non-motor symptoms before diagnosis. The SOC model further predicts that body-first patients are older, more commonly develop symmetric dopaminergic degeneration, and are at increased risk of dementia-compared to brain-first patients. In this review, the SOC model is explained and compared to alternative models of the pathogenesis of Lewy body disorders, including the Braak staging system, and the Unified Staging System for Lewy Body Disorders. Postmortem evidence from brain banks and clinical imaging data of dopaminergic and cardiac sympathetic loss is reviewed. It is concluded that these datasets seem to be more compatible with the SOC model than with those alternative disease models of Lewy body disorders.

Topics: alpha-Synuclein; Brain; Humans; Lewy Body Disease; Parkinson Disease; REM Sleep Behavior Disorder

Since the description of some peculiar symptoms by James Parkinson in 1817, attempts have been made to define its cause or at least to enlighten the pathology of "Parkinson's disease (PD)." The vast majority of PD subtypes and most cases of sporadic PD share Lewy bodies (LBs) as a characteristic pathological hallmark. However, the processes underlying LBs generation and its causal triggers are still unknown. ɑ-Synuclein (ɑ-syn, encoded by the SNCA gene) is a major component of LBs, and SNCA missense mutations or duplications/triplications are causal for rare hereditary forms of PD. Thus, it is imperative to study ɑ-syn protein and its pathology, including oligomerization, fibril formation, aggregation, and spreading mechanisms. Furthermore, there are synergistic effects in the underlying pathogenic mechanisms of PD, and multiple factors-contributing with different ratios-appear to be causal pathological triggers and progression factors. For example, oxidative stress, reduced antioxidative capacity, mitochondrial dysfunction, and proteasomal disturbances have each been suggested to be causal for ɑ-syn fibril formation and aggregation and to contribute to neuroinflammation and neural cell death. Aging is also a major risk factor for PD. Iron, as well as neuromelanin (NM), show age-dependent increases, and iron is significantly increased in the Parkinsonian substantia nigra (SN). Iron-induced pathological mechanisms include changes of the molecular structure of ɑ-syn. However, more recent PD research demonstrates that (i) LBs are detected not only in dopaminergic neurons and glia but in various neurotransmitter systems, (ii) sympathetic nerve fibres degenerate first, and (iii) at least in "brain-first" cases dopaminergic deficiency is evident before pathology induced by iron and NM. These recent findings support that the ɑ-syn/LBs pathology as well as iron- and NM-induced pathology in "brain-first" cases are important facts of PD pathology and via their interaction potentiate the disease process in the SN. As such, multifactorial toxic processes posted on a personal genetic risk are assumed to be causal for the neurodegenerative processes underlying PD. Differences in ratios of multiple factors and their spatiotemporal development, and the fact that common triggers of PD are hard to identify, imply the existence of several phenotypical subtypes, which is supported by arguments from both the "bottom-up/dual-hit" and "brain-first" models. Therapeutic strategie

Topics: alpha-Synuclein; Humans; Inflammation; Iron; Lewy Bodies; Parkinson Disease

The Parkinson's disease (PD) research field has seen the advent of several promising biomarkers and a deeper understanding of the clinical features of the disease from the earliest stages of pathology to manifest disease. Despite progress, a biologically based PD staging system does not exist. Such staging would be a useful framework within which to model the disease, develop and validate biomarkers, guide therapeutic development, and inform clinical trials design. We propose that the presence of aggregated neuronal α-synuclein, dopaminergic neuron dysfunction/degeneration, and clinical signs and symptoms identifies a group of individuals that have Lewy body pathology, which in early stages manifests with what is now referred to as prodromal non-motor features and later stages with the manifestations of PD and related Lewy body diseases as defined by clinical diagnostic criteria. Based on the state of the field, we herein propose a definition and staging of PD based on biology. We present the biologic basis for such a staging system and review key assumptions and evidence that support the proposed approach. We identify gaps in knowledge and delineate crucial research priorities that will inform the ultimate integrated biologic staging system for PD.

Topics: alpha-Synuclein; Biological Products; Biomarkers; Humans; Lewy Bodies; Lewy Body Disease; Nerve Degeneration; Parkinson Disease; Prodromal Symptoms

Emerging evidence implicates intestinal involvement in the onset and/or progression on the selective degeneration of dopaminergic neurons characterizing Parkinson's disease (PD). On the one hand, there are studies supporting the Braak hypothesis that holds that pathologic α-synuclein, a hallmark of PD, is secreted by enteric nerves into intestinal tissue and finds its way to the central nervous system (CNS) via retrograde movement in the vagus nerve. On the other hand, there is data showing that cells bearing leucine-rich repeat kinase 2 (LRRK2), a signaling molecule with genetic variants associated with both PD and with inflammatory bowel disease, can be activated in intestinal tissue and contribute locally to intestinal inflammation, or peripherally to PD pathogenesis via cell trafficking to the CNS. Importantly, these gut-centered factors affecting PD development are not necessarily independent of one another: they may interact and enhance their respective pathologic functions. In this review, we discuss this possibility by analysis of studies conducted in recent years focusing on the ability of LRRK2 to shape immunologic responses and the role of α-synuclein in influencing this ability.

Topics: alpha-Synuclein; Brain-Gut Axis; Dopaminergic Neurons; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Parkinson Disease; Signal Transduction

The GBA1 gene encodes the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. Biallelic variants in GBA1 cause Gaucher disease (GD), a lysosomal storage disorder characterised by loss of GCase activity and aberrant intracellular accumulation of GCase substrates. Carriers of GBA1 variants have an increased risk of developing Parkinson disease (PD), with odds ratio ranging from 2.2 to 30 according to variant severity. GBA1 variants which do not cause GD in homozygosis can also increase PD risk. Patients with PD carrying GBA1 variants show a more rapidly progressive phenotype compared to non-carriers, emphasising the need for disease modifying treatments targeting the GBA1 pathway. Several mechanisms secondary to GCase dysfunction are potentially responsible for the pathological changes leading to PD. Misfolded GCase proteins induce endoplasmic reticulum stress and subsequent unfolded protein response and impair the autophagy-lysosomal pathway. This results in α-synuclein accumulation and spread, and promotes neurodegenerative changes. Preclinical evidence also shows that products of GCase activity can promote accumulation of α-synuclein, however there is no convincing evidence of substrate accumulation in GBA1-PD brains. Altered lipid homeostasis secondary to loss of GCase activity could also contribute to PD pathology. Treatments that target the GBA1 pathway could reverse these pathological processes and halt/slow the progression of PD. These range from augmentation of GCase activity via GBA1 gene therapy, restoration of normal intracellular GCase trafficking via molecular chaperones, and substrate reduction therapy. This review discusses the pathways associated with GBA1-PD and related novel GBA1-targeted interventions for PD treatment.

Topics: alpha-Synuclein; Brain; Glucosylceramidase; Humans; Mutation; Parkinson Disease

Alpha-synuclein (α-Syn) is a short presynaptic protein with an active role on synaptic vesicle traffic and the neurotransmitter release and reuptake cycle. The α-Syn pathology intertwines with the formation of Lewy Bodies (multiprotein intraneuronal aggregations), which, combined with inflammatory events, define various α-synucleinopathies, such as Parkinson's Disease (PD). In this review, we summarize the current knowledge on α-Syn mechanistic pathways to inflammation, as well as the eventual role of microbial dysbiosis on α-Syn. Furthermore, we explore the possible influence of inflammatory mitigation on α-Syn. In conclusion, and given the rising burden of neurodegenerative disorders, it is pressing to clarify the pathophysiological processes underlying α-synucleinopathies, in order to consider the mitigation of existing low-grade chronic inflammatory states as a potential pathway toward the management and prevention of such conditions, with the aim of starting to search for concrete clinical recommendations in this particular population.

Topics: alpha-Synuclein; Humans; Inflammation; Lewy Bodies; Parkinson Disease; Synucleinopathies

Parkinson's disease (PD) is a progressive neurodegenerative disorder clinically defined by motor instability, bradykinesia, and resting tremors. The clinical symptomatology is seen alongside pathologic changes, most notably the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of α-synuclein and neuromelanin aggregates throughout numerous neural circuits. Traumatic brain injury (TBI) has been implicated as a risk factor for developing various neurodegenerative diseases, with the most compelling argument for the development of PD. Dopaminergic abnormalities, the accumulation of α-synuclein, and disruptions in neural homeostatic mechanisms, including but not limited to the release of pro-inflammatory mediators and the production of reactive oxygen species (ROS), are all present following TBI and are closely related to the pathologic changes seen in PD. Neuronal iron accumulation is discernable in degenerative and injured brain states, as is aquaporin-4 (APQ4). APQ4 is an essential mediator of synaptic plasticity in PD and regulates edematous states in the brain after TBI. Whether the cellular and parenchymal changes seen post-TBI directly cause neurodegenerative diseases such as PD is a point of considerable interest and debate; this review explores the vast array of neuroimmunological interactions and subsequent analogous changes that occur in TBI and PD. There is significant interest in exploring the validity of the relationship between TBI and PD, which is a focus of this review.

Topics: alpha-Synuclein; Brain Injuries, Traumatic; Dopaminergic Neurons; Humans; Neurodegenerative Diseases; Neuroimmunomodulation; Parkinson Disease; Substantia Nigra

Parkinson's disease (PD) is a multifactorial disorder involving both motor and non-motor symptoms caused by the progressive death of distinct neuronal populations, including dopaminergic neurons in the substantia nigra. The deposition of aggregated α-synuclein protein into Lewy body inclusions is a hallmark of the disorder, and α-synuclein pathology has been found in the enteric nervous system (ENS) of PD patients up to two decades prior to diagnosis. In combination with the high occurrence of gastrointestinal dysfunction in early stages of PD, current evidence strongly suggests that some forms of PD may originate in the gut. In this review, we discuss human studies that support ENS Lewy pathology as a characteristic feature of PD, and present evidence from humans and animal model systems that α-synuclein aggregation may follow a prion-like spreading cascade from enteric neurons, through the vagal nerve, and into the brain. Given the accessibility of the human gut to pharmacologic and dietary interventions, therapeutic strategies aimed at reducing pathological α-synuclein in the gastrointestinal tract hold significant promise for PD treatment.

Topics: alpha-Synuclein; Animals; Brain; Dopaminergic Neurons; Humans; Parkinson Disease; Prions

There is strong support from studies in humans and in animal models that Parkinson's disease (PD) may begin in the gut. This brings about a unique opportunity for researchers in the field of neurogastroenterology to contribute to advancing the field and making contributions that could lead to the ability to diagnose and treat PD in the premotor stages. Lack of familiarity with some of the aspects of the experimental approaches used in these studies may present a barrier for neurogastroenterology researchers to enter the field. Much remains to be understood about intestinal-specific components of gut-first PD pathogenesis and the field would benefit from contributions of enteric and central nervous system neuroscientists.. To address these issues, we have conducted a systematic review of the two most frequently used experimental models of gut-first PD: transneuronal propagation of α-synuclein preformed fibrils and oral exposure to environmental toxins. We have reviewed the details of these studies and present methodological considerations for the use of these models. Our aim is that this review will serve as a framework and useful reference for neuroscientists, gastroenterologists, and neurologists interested in applying their expertise to advancing our understanding of gut-first PD.

Topics: alpha-Synuclein; Animals; Brain; Central Nervous System; Humans; Models, Theoretical; Parkinson Disease

Several advances in fluid and tissue-based biomarkers for use in Parkinson's disease (PD) and other synucleinopathies have been made in the last several years. While work continues on species of alpha-synuclein (aSyn) and other proteins which can be measured from spinal fluid and plasma samples, immunohistochemistry and immunofluorescence from peripheral tissue biopsies and alpha-synuclein seeding amplification assays (aSyn-SAA: including real-time quaking induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA)) now offer a crucial advancement in their ability to identify aSyn species in PD patients in a categorical fashion (i.e., of aSyn + vs aSyn -); to augment clinical diagnosis however, aSyn-specific assays that have quantitative relevance to pathological burden remain an unmet need. Alzheimer's disease (AD) co-pathology is commonly found postmortem in PD, especially in those who develop dementia, and dementia with Lewy bodies (DLB). Biofluid biomarkers for tau and amyloid beta species can detect AD co-pathology in PD and DLB, which does have relevance for prognosis, but further work is needed to understand the interplay of aSyn tau, amyloid beta, and other pathological changes to generate comprehensive biomarker profiles for patients in a manner translatable to clinical trial design and individualized therapies.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Biopsy; Humans; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disorder that has a high incidence during the aging process and is characterized by the loss of dopaminergic neurons in the substantia nigra, leading to motor dysfunctions and non‑motor symptoms. Impaired clearance and excessive accumulation of aberrantly modified proteins or damaged organelles, such as aggregated α‑synuclein and dysfunctional mitochondria, are regarded as the main causes of nigrostriatal neurodegeneration. As one of the major degradation pathways, autophagy can recycle these useless or toxic substances to maintain cellular homeostasis and it plays a crucial role in PD progression. MicroRNAs (miRNAs) are a group of small non‑coding RNA molecules that regulate gene expression by silencing targeted mRNAs. Recent studies have illustrated that autophagy‑regulating miRNA has been implicated in pathological processes of PD, including α‑synuclein accumulation, mitochondrial damage, neuroinflammation and neuronal apoptosis, which suggests that targeting autophagy‑regulating miRNAs may provide novel therapeutic strategies for this disease. The present review summarizes the role of autophagy in PD and emphasizes the role of miRNA‑mediated autophagy in PD, for the development of promising interventions in this disease.

Topics: alpha-Synuclein; Autophagy; Dopaminergic Neurons; Humans; MicroRNAs; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, and its prevalence is increasing with age. A wealth of genetic evidence indicates that the endo-lysosomal system is a major pathway driving PD pathogenesis with a growing number of genes encoding endo-lysosomal proteins identified as risk factors for PD, making it a promising target for therapeutic intervention. However, detailed knowledge and understanding of the molecular mechanisms linking these genes to the disease are available for only a handful of them (e.g. LRRK2, GBA1, VPS35). Taking on the challenge of studying poorly characterized genes and proteins can be daunting, due to the limited availability of tools and knowledge from previous literature. This review aims at providing a valuable source of molecular and cellular insights into the biology of lesser-studied PD-linked endo-lysosomal genes, to help and encourage researchers in filling the knowledge gap around these less popular genetic players. Specific endo-lysosomal pathways discussed range from endocytosis, sorting, and vesicular trafficking to the regulation of membrane lipids of these membrane-bound organelles and the specific enzymatic activities they contain. We also provide perspectives on future challenges that the community needs to tackle and propose approaches to move forward in our understanding of these poorly studied endo-lysosomal genes. This will help harness their potential in designing innovative and efficient treatments to ultimately re-establish neuronal homeostasis in PD but also other diseases involving endo-lysosomal dysfunction.

Topics: alpha-Synuclein; Endocytosis; Endosomes; Humans; Lysosomes; Neurodegenerative Diseases; Parkinson Disease

The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins are found in, and released from, the outer membrane of Gram-negative bacteria, for example in the gut. It is proposed that gut dysfunction in early PD leads to elevated LPS levels in the gut wall and blood, which promotes both α-synuclein aggregation in the enteric neurons and a peripheral inflammatory response. Communication to the brain via circulating LPS and cytokines in the blood and/or the gut-brain axis leads to neuroinflammation and spreading of α-synuclein pathology, exacerbating neurodegeneration in brainstem nuclei and loss of dopaminergic neurons in the substantia nigra, and manifesting in the clinical symptoms of PD. The evidence supporting this hypothesis includes: (1) gut dysfunction, permeability, and bacterial changes occur early in PD, (2) serum levels of LPS are increased in a proportion of PD patients, (3) LPS induces α-synuclein expression, aggregation, and neurotoxicity, (4) LPS causes activation of peripheral monocytes leading to inflammatory cytokine production, and (5) blood LPS causes brain inflammation and specific loss of midbrain dopaminergic neurons, mediated by microglia. If the hypothesis is correct, then treatment options might include: (1) changing the gut microbiome, (2) reducing gut permeability, (3) reducing circulating LPS levels, or (4) blocking the response of immune cells and microglia to LPS. However, the hypothesis has a number of limitations and requires further testing, in particular whether reducing LPS levels can reduce PD incidence, progression, or severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Dopaminergic Neurons; Endotoxins; Humans; Lipopolysaccharides; Parkinson Disease

The heterogeneity of Parkinson's disease (PD), i.e. the various clinical phenotypes, pathological findings, genetic predispositions and probably also the various implicated pathophysiological pathways pose a major challenge for future research projects and therapeutic trail design. We outline several pathophysiological concepts, pathways and mechanisms, including the presumed roles of α-synuclein misfolding and aggregation, Lewy bodies, oxidative stress, iron and melanin, deficient autophagy processes, insulin and incretin signaling, T-cell autoimmunity, the gut-brain axis and the evidence that microbial (viral) agents may induce molecular hallmarks of neurodegeneration. The hypothesis is discussed, whether PD might indeed be triggered by exogenous (infectious) agents in susceptible individuals upon entry via the olfactory bulb (brain first) or the gut (body-first), which would support the idea that disease mechanisms may change over time. The unresolved heterogeneity of PD may have contributed to the failure of past clinical trials, which attempted to slow the course of PD. We thus conclude that PD patients need personalized therapeutic approaches tailored to specific phenomenological and etiologic subtypes of disease.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Parkinson Disease; T-Lymphocytes

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is currently no disease-modifying treatment to halt neuronal loss in PD. A major hurdle for developing and testing such curative therapies results from the fact that most DA neurons are already lost at the time of the clinical diagnosis, rendering them inaccessible to therapy. Understanding the early pathological changes that precede Lewy body pathology (LBP) and cell loss in PD will likely support the identification of novel diagnostic and therapeutic strategies and help to differentiate LBP-dependent and -independent alterations. Several previous studies identified such specific molecular and cellular changes that occur prior to the appearance of Lewy bodies (LBs) in DA neurons, but a concise map of such early disease events is currently missing.. Here, we conducted a literature review to identify and discuss the results of previous studies that investigated cases with incidental Lewy body disease (iLBD), a presumed pathological precursor of PD.. Collectively, our review demonstrates numerous cellular and molecular neuropathological changes occurring prior to the appearance of LBs in DA neurons.. Our review provides the reader with a summary of early pathological events in PD that may support the identification of novel therapeutic and diagnostic targets and aid to the development of disease-modifying strategies in PD.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Lewy Body Disease; Nerve Degeneration; Neuropathology; Parkinson Disease

The misfolding and subsequent abnormal accumulation and aggregation of α-Synuclein (αSyn) as insoluble fibrils in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson's disease (PD) and several neurodegenerative disorders. A combination of environmental and genetic factors is linked to αSyn misfolding, among which neuroinflammation is recognized to play an important role. Indeed, a number of studies indicate that a Toll-like receptor (TLR)-mediated neuroinflammation might lead to a dopaminergic neural loss, suggesting that TLRs could participate in the pathogenesis of PD as promoters of immune/neuroinflammatory responses. Here we will summarize our current understanding on the mechanisms of αSyn aggregation and misfolding, focusing on the contribution of TLRs to the progression of α-synucleinopathies and speculating on their link with the non-motor disturbances associated with aging and neurodegenerative disorders.

Topics: alpha-Synuclein; Humans; Inflammation; Lewy Bodies; Neuroinflammatory Diseases; Parkinson Disease; Synucleinopathies

The critical role of alpha-synuclein in Parkinson's disease represents a pivotal discovery. Some progress has been made over recent years in identifying disease-modifying therapies for Parkinson's disease that target alpha-synuclein. However, these treatments have not yet shown clear efficacy in slowing the progression of this disease. Several explanations exist for this issue. The pathogenesis of Parkinson's disease is complex and not yet fully clarified and the heterogeneity of the disease, with diverse genetic susceptibility and risk factors and different clinical courses, adds further complexity. Thus, a deep understanding of alpha-synuclein physiological and pathophysiological functions is crucial. In this review, we first describe the cellular and animal models developed over recent years to study the physiological and pathological roles of this protein, including transgenic techniques, use of viral vectors and intracerebral injections of alpha-synuclein fibrils. We then provide evidence that these tools are crucial for modelling Parkinson's disease pathogenesis, causing protein misfolding and aggregation, synaptic dysfunction, brain plasticity impairment and cell-to-cell spreading of alpha-synuclein species. In particular, we focus on the possibility of dissecting the pre- and postsynaptic effects of alpha-synuclein in both physiological and pathological conditions. Finally, we show how vulnerability of specific neuronal cell types may facilitate systemic dysfunctions leading to multiple network alterations. These functional alterations underlie diverse motor and non-motor manifestations of Parkinson's disease that occur before overt neurodegeneration. However, we now understand that therapeutic targeting of alpha-synuclein in Parkinson's disease patients requires caution, since this protein exerts important physiological synaptic functions. Moreover, the interactions of alpha-synuclein with other molecules may induce synergistic detrimental effects. Thus, targeting only alpha-synuclein might not be enough. Combined therapies should be considered in the future.

Topics: alpha-Synuclein; Animals; Animals, Genetically Modified; Disease Models, Animal; Humans; Neurons; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Inflammation has been observed in both the idiopathic and familial forms of PD. Importantly, PD is reported more often in men than in women, men having at least 1.5- fold higher risk to develop PD than women. This review summarizes the impact of biological sex and sex hormones on the neuroimmune contributions to PD and its investigation in animal models of PD. Innate and peripheral immune systems participate in the brain neuroinflammation of PD patients and is reproduced in neurotoxin, genetic and α-synuclein based models of PD. Microglia and astrocytes are the main cells of the innate immune system in the central nervous system and are the first to react to restore homeostasis in the brain. Analysis of serum immunoprofiles in female and male control and PD patients show that a great proportion of these markers differ between males and females. The relationship between cerebrospinal fluid inflammatory markers and PD clinical characteristics or PD biomarkers shows sex differences. Conversely, in animal models of PD, sex differences in inflammation are well documented and the beneficial effects of endogenous and exogenous estrogenic modulation in inflammation have been reported. Targeting neuroinflammation in PD is an emerging therapeutic option but gonadal drugs have not yet been investigated in this respect, thus offering new opportunities for sex specific treatments.

Topics: alpha-Synuclein; Animals; Brain; Female; Inflammation; Male; Microglia; Neurodegenerative Diseases; Neuroinflammatory Diseases; Parkinson Disease

Parkinson's disease (PD) is characterized by fibrillation of disordered proteins known as Lewy bodies in the substantia nigra that also undergo progressive neurodegeneration. The aggregation of α-synuclein (α-syn) is a hallmark and potentially a critical step in the development of Parkinson's disease and other synucleinopathies. The synaptic vesicle protein α-syn is a small, abundant, highly conserved disordered protein and the causative agent of neurodegenerative diseases. Several novel pharmacologically active compounds are used to treat PD and other neurodegenerative disorders. Though, the mechanism through which these molecules inhibit the α-syn aggregation is still not fully understood.. This review article is focused on the recent advancements in compounds that can inhibit the development of α-syn fibrillation and oligomerization.. The current review article is based on the most recent and frequently cited papers from Google Scholar, SciFinder, and Researchgate sources.. In the progression of PD, the mechanism of α-syn aggregation involves the structural transformation from monomers into amyloid fibrils. As the accumulation of α-syn in the brain has been linked to many disorders, the recent search for disease-modifying medications mainly focused on modifying the α-syn aggregation. This review contains a detailed report of literature findings and illustrates the unique structural features, structure-activity relationship, and therapeutic potential of the natural flavonoids in the inhibition of α-syn are also discussed.. Recently, many naturally occurring molecules such as curcumin, polyphenols, nicotine, EGCG, and stilbene have been recognized to inhibit the fibrillation and toxicity of α-syn. Therefore, knowing the α-synuclein filament's structure and how they originate will help invent particular biomarkers for synucleinopathies and develop reliable and effective mechanism-based therapeutics. We hope the information this review provides may help evaluate novel chemical compounds, such as α- syn aggregation inhibitors, and will contribute to developing novel drugs for treating Parkinson's disease.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Neurodegenerative Diseases; Parkinson Disease; Synucleinopathies

Recently, a large number of experimenters have found that the pathogenesis of Parkinson's disease may be related to the gut microbiome and proposed the microbiome-gut-brain axis. Studies have shown that Toll-like receptors, especially Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4), are key mediators of gut homeostasis. In addition to their established role in innate immunity throughout the body, research is increasingly showing that the Toll-like receptor 2 and Toll-like receptor 4 signaling pathways shape the development and function of the gut and enteric nervous system. Notably, Toll-like receptor 2 and Toll-like receptor 4 are dysregulated in Parkinson's disease patients and may therefore be identified as the core of early gut dysfunction in Parkinson's disease. To better understand the contribution of Toll-like receptor 2 and Toll-like receptor 4 dysfunction in the gut to early α-synuclein aggregation, we discussed the structural function of Toll-like receptor 2 and Toll-like receptor 4 and signal transduction of Toll-like receptor 2 and Toll-like receptor 4 in Parkinson's disease by reviewing clinical, animal models, and

Topics: alpha-Synuclein; Animals; Brain-Gut Axis; Parkinson Disease; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Genetic predisposition and immune dysfunction are involved in the pathogenesis of PD. Notably, peripheral inflammatory disorders and neuroinflammation are associated with PD neuropathology. Type 2 diabetes mellitus (T2DM) is associated with inflammatory disorders due to hyperglycaemia-induced oxidative stress and the release of pro-inflammatory cytokines. Particularly, insulin resistance (IR) in T2DM promotes the degeneration of dopaminergic neurons in the substantia nigra (SN). Thus, T2DM-induced inflammatory disorders predispose to the development and progression of PD, and their targeting may reduce PD risk in T2DM. Therefore, this narrative review aims to find the potential link between T2DM and PD by investigating the role of inflammatory signalling pathways, mainly the nuclear factor kappa B (NF-κB) and the nod-like receptor pyrin 3 (NLRP3) inflammasome. NF-κB is implicated in the pathogenesis of T2DM, and activation of NF-κB with induction of neuronal apoptosis was also confirmed in PD patients. Systemic activation of NLRP3 inflammasome promotes the accumulation of α-synuclein and degeneration of dopaminergic neurons in the SN. Increasing α-synuclein in PD patients enhances NLRP3 inflammasome activation and the release of interleukin (IL)-1β followed by the development of systemic inflammation and neuroinflammation. In conclusion, activation of the NF-κB/NLRP3 inflammasome axis in T2DM patients could be the causal pathway in the development of PD. The inflammatory mechanisms triggered by activated NLRP3 inflammasome lead to pancreatic β-cell dysfunction and the development of T2DM. Therefore, attenuation of inflammatory changes by inhibiting the NF-κB/NLRP3 inflammasome axis in the early T2DM may reduce future PD risk.

Topics: alpha-Synuclein; Diabetes Mellitus, Type 2; Humans; Inflammasomes; Neurodegenerative Diseases; Neuroinflammatory Diseases; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; NLR Proteins; Parkinson Disease; Pyrin

Parkinson's disease (PD) is the second most prevailing progressive disorder leading to neurodegeneration, typically in people above 65 years of age. Motor clinical manifestations of PD appear in a much later stage and include rigidity, tremors, akinesia, and gait dysfunction. There are also nonmotor symptoms like GI and olfactory dysfunction. However, they cannot be considered for diagnosis of the disease, as they are unspecific. PD pathogenesis is mainly characterized by deposits of inclusion bodies on dopaminergic (DA) neurons in substantia nigra pars compacta region (SNpc) of the brain. The major component of these inclusion bodies, are α-synuclein aggregates. α-Synuclein undergoes misfolding and oligomerization to form aggregates and fibrils. These aggregates gradually propagate PD pathology. Other prominent features of this pathological development include mitochondrial dysfunction, neuroinflammation, oxidative stress, and impaired autophagy. These all contribute to neuronal degeneration. Besides this, there are many underlying factors which influence these processes. These factors comprise molecular proteins and signaling cascades. In this review, we have listed out underexplored molecular targets that may aid in development of neoteric and advanced therapeutics.

Topics: alpha-Synuclein; Brain; Dopaminergic Neurons; Humans; Parkinson Disease; Pars Compacta

Disease modeling in non-human subjects is an essential part of any clinical research. To gain proper understanding of the etiology and pathophysiology of any disease, experimental models are required to replicate the disease process. Due to the huge diversity in pathophysiology and prognosis in different diseases, animal modeling is customized and specific accordingly. As in other neurodegenerative diseases, Parkinson's disease is a progressive disorder coupled with varying forms of physical and mental disabilities. The pathological hallmarks of Parkinson's disease are associated with the accumulation of misfolded protein called α-synuclein as Lewy body, and degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) area affecting the patient's motor activity. Extensive research has already been conducted regarding animal modeling of Parkinson's diseases. These include animal systems with induction of Parkinson's, either pharmacologically or via genetic manipulation. In this review, we will be summarizing and discussing some of the commonly employed Parkinson's disease animal model systems and their applications and limitations.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Dopaminergic Neurons; Lewy Bodies; Parkinson Disease; Pars Compacta; Substantia Nigra

Parkinson's disease is a neurodegenerative disease affecting mainly the elderly population. It is characterized by the loss of dopaminergic neurons of the substantia nigra pars compacta region. Parkinson's disease patients exhibit motor symptoms like tremors, rigidity, bradykinesia/hypokinesia, and non-motor symptoms like depression, cognitive decline, delusion, and pain. Major pathophysiological factors which contribute to neuron loss include excess/misfolded alpha-synuclein aggregates, microglial cell-mediated neuroinflammation, excitotoxicity, oxidative stress, and defective mitochondrial function. Sigma-1 receptors are molecular chaperones located at mitochondria-associated ER membrane. Their activation (by endogenous ligands or agonists) has shown neuroprotective and neurorestorative effects in various diseases. This review discusses the roles of activated Sig-1 receptors in modulating various pathophysiological features of Parkinson's disease like alpha-synuclein aggregates, neuroinflammation, excitotoxicity, and oxidative stress.

Topics: Aged; alpha-Synuclein; Dopaminergic Neurons; Humans; Neurodegenerative Diseases; Neuroinflammatory Diseases; Parkinson Disease; Sigma-1 Receptor; Substantia Nigra

Oligomerization and aggregation of misfolded forms of α-synuclein are believed to be key molecular mechanisms in Parkinson's disease (PD) and other synucleinopathies, so extensive research has attempted to understand these processes. Among diverse post-translational modifications that impact α-synuclein aggregation, glycation may take place at several lysine sites and modify α-synuclein oligomerization, toxicity, and clearance. The receptor for advanced glycation end products (RAGE) is considered a key regulator of chronic neuroinflammation through microglial activation in response to advanced glycation end products, such as carboxy-ethyl-lysine, or carboxy-methyl-lysine. The presence of RAGE in the midbrain of PD patients has been reported in the last decades and this receptor was proposed to have a role in sustaining PD neuroinflammation. However, different PD animal models demonstrated that RAGE is preferentially expressed in neurons and astrocytes, while recent evidence demonstrated that fibrillar, non-glycated α-synuclein binds to RAGE. Here, we summarize the available data on α-synuclein glycation and RAGE in the context of PD, and discuss about the questions yet to be answered that may increase our understanding of the molecular bases of PD and synucleinopathies.

Topics: alpha-Synuclein; Animals; Lysine; Maillard Reaction; Neuroinflammatory Diseases; Parkinson Disease; Receptor for Advanced Glycation End Products; Synucleinopathies

In 2020, more than 9 million patients suffering from Parkinson's disease (PD) were reported worldwide, and studies predict that the burden of this disease will grow substantially in industrial countries. In the last decade, there has been a better understanding of this neurodegenerative disorder, clinically characterized by motor disturbances, impaired balance, coordination, memory difficulties, and behavioral changes. Various preclinical investigations and studies on human postmortem brains suggest that local oxidative stress and inflammation promote misfolding and aggregation of alpha-synuclein within Lewy bodies and cause nerve cell damage. Parallel to these investigations, the familial contribution to the disease became evident from studies on genome-wide association in which specific genetic defects were linked to neuritic alpha-synuclein pathology. As for treatment, currently available pharmacological and surgical interventions may improve the quality of life but do not stop the progress of neurodegeneration. However, numerous preclinical studies have provided insights into the pathogenesis of PD. Their results provide a solid base for clinical trials and further developments. In this review, we discuss the pathogenesis, the prospects, and challenges of synolytic therapy, CRISPR, gene editing, and gene- and cell-based therapy. We also throw light on the recent observation that targeted physiotherapy may help improve the gait and other motor impairments.

Topics: alpha-Synuclein; Brain; Genome-Wide Association Study; Humans; Parkinson Disease; Quality of Life

The aberrant aggregation of α-Synuclein (αS), a disordered protein primarily localised at the neuronal synapses, is associated with a number of neurodegenerative disorders including Parkinson's disease (PD). The biological properties of αS are strictly connected with its ability to bind synaptic membranes under both physiological and pathological conditions. Here we overview the recent studies on the structural and biological properties of the membrane interaction by αS. The characterisation of this state is particularly challenging as the membrane binding of αS is weak, transient and features a considerable degree of conformational disorder. Advancements in this area have been achieved through combinations of nuclear magnetic resonance (NMR), super-resolution microscopy, cryo-EM and cellular biophysics. Current data clarified the central role of the equilibrium between ordered and disordered states of αS at the membrane surface, which regulates the membrane affinity, the aggregation into amyloid fibrils and the promotion of vesicle clustering. Recent results on toxic oligomeric species of αS also revealed common features in the membrane interaction of functional and aberrant forms of this protein. These findings therefore evidence the challenging nature of identifying suitable therapeutics to target the aberrant aggregation of αS in PD while leaving its normal physiological form unperturbed.

Topics: alpha-Synuclein; Cell Membrane; Humans; Magnetic Resonance Spectroscopy; Parkinson Disease; Protein Binding

Endocytosis is the fundamental uptake process through which cells internalize extracellular materials and species. Neurodegenerative diseases (NDs) are characterized by a progressive accumulation of intrinsically disordered protein species, leading to neuronal death. Misfolding in many proteins leads to various NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other disorders. Despite the significance of disordered protein species in neurodegeneration, their spread between cells and the cellular uptake of extracellular species is not entirely understood. This review discusses the major internalization mechanisms of the different conformer species of these proteins and their endocytic mechanisms. We briefly introduce the broad types of endocytic mechanisms found in cells and then summarize what is known about the endocytosis of monomeric, oligomeric and aggregated conformations of tau, Aβ, α-Syn, Huntingtin, Prions, SOD1, TDP-43 and other proteins associated with neurodegeneration. We also highlight the key players involved in internalizing these disordered proteins and the several techniques and approaches to identify their endocytic mechanisms. Finally, we discuss the obstacles involved in studying the endocytosis of these protein species and the need to develop better techniques to elucidate the uptake mechanisms of a particular disordered protein species.

Topics: alpha-Synuclein; Alzheimer Disease; Humans; Neurodegenerative Diseases; Parkinson Disease; Protein Aggregates

Parkinsonian disorders, such as Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), share early motor symptoms but have distinct pathophysiology. As a result, accurate premortem diagnosis is challenging for neurologists, hindering efforts for disease-modifying therapeutic discovery. Extracellular vesicles (EVs) contain cell-state-specific biomolecules and can cross the blood-brain barrier to the peripheral circulation, providing a unique central nervous system (CNS) insight. This meta-analysis evaluated blood-isolated neuronal and oligodendroglial EVs (nEVs and oEVs) α-synuclein levels in Parkinsonian disorders.. Following PRISMA guidelines, the meta-analysis included 13 studies. An inverse-variance random-effects model quantified effect size (SMD), QUADAS-2 assessed risk of bias and publication bias was evaluated. Demographic and clinical variables were collected for meta-regression.. The meta-analysis included 1,565 patients with PD, 206 with MSA, 21 with DLB, 172 with PSP, 152 with CBS and 967 healthy controls (HCs). Findings suggest that combined concentrations of nEVs and oEVs α-syn is higher in patients with PD compared to HCs (SMD = 0.21, p = 0.021), while nEVs α-syn is lower in patients with PSP and CBS compared to patients with PD (SMD = -1.04, p = 0.0017) or HCs (SMD = -0.41, p < 0.001). Additionally, α-syn in nEVs and/or oEVs did not significantly differ in patients with PD vs. MSA, contradicting the literature. Meta-regressions show that demographic and clinical factors were not significant predictors of nEVs or oEVs α-syn concentrations.. The results highlight the need for standardized procedures and independent validations in biomarker studies and the development of improved biomarkers for distinguishing Parkinsonian disorders.

Topics: alpha-Synuclein; Biomarkers; Central Nervous System; Extracellular Vesicles; Humans; Multiple System Atrophy; Parkinson Disease; Parkinsonian Disorders

The accumulation of proteinaceous inclusions in the brain is a common feature among neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), and dementia with Lewy bodies (DLB). The main neuropathological hallmark of PD and DLB are inclusions, known as Lewy bodies (LBs), enriched not only in α-synuclein (aSyn), but also in lipid species, organelles, membranes, and even nucleic acids. Furthermore, several genetic risk factors for PD are mutations in genes involved in lipid metabolism, such as GBA1, VSP35, or PINK1. Thus, it is not surprising that mechanisms that have been implicated in PD, such as inflammation, altered intracellular and vesicular trafficking, mitochondrial dysfunction, and alterations in the protein degradation systems, may be also directly or indirectly connected through lipid homeostasis. In this review, we highlight and discuss the recent evidence that suggests lipid biology as important drivers of PD, and which require renovated attention by neuropathologists. Particularly, we address the implication of lipids in aSyn accumulation and in the spreading of aSyn pathology, in mitochondrial dysfunction, and in ER stress. Together, this suggests we should broaden the view of PD not only as a proteinopathy but also as a lipidopathy.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Lipids; Parkinson Disease; Proteostasis Deficiencies; Synucleinopathies

Synucleinopathies are a group of neurodegenerative disorders, classically characterized by the accumulation of aggregated alpha synuclein (aSyn) in the central nervous system. Parkinson's disease (PD) and multiple system atrophy (MSA) are the two prominent members of this family. Current treatment options mainly focus on the motor symptoms of these diseases. However, non-motor symptoms, including gastrointestinal (GI) symptoms, have recently gained particular attention, as they are frequently associated with synucleinopathies and often arise before motor symptoms. The gut-origin hypothesis has been proposed based on evidence of an ascending spreading pattern of aggregated aSyn from the gut to the brain, as well as the comorbidity of inflammatory bowel disease and synucleinopathies. Recent advances have shed light on the mechanisms underlying the progression of synucleinopathies along the gut-brain axis. Given the rapidly expanding pace of research in the field, this review presents a summary of the latest findings on the gut-to-brain spreading of pathology and potential pathology-reinforcing mediators in synucleinopathies. Here, we focus on 1) gut-to-brain communication pathways, including neuronal pathways and blood circulation, and 2) potential molecular signalling mediators, including bacterial amyloid proteins, microbiota dysbiosis-induced alterations in gut metabolites, as well as host-derived effectors, including gut-derived peptides and hormones. We highlight the clinical relevance and implications of these molecular mediators and their possible mechanisms in synucleinopathies. Moreover, we discuss their potential as diagnostic markers in distinguishing the subtypes of synucleinopathies and other neurodegenerative diseases, as well as for developing novel individualized therapeutic options for synucleinopathies.

Topics: alpha-Synuclein; Brain; Humans; Multiple System Atrophy; Neurons; Parkinson Disease; Synucleinopathies

Parkinson's disease (PD) is an incurable neurodegenerative disease that is rarely diagnosed at an early stage. Although the understanding of PD-related mechanisms has greatly improved over the last decade, the diagnosis of PD is still based on neurological examination through the identification of motor symptoms, including bradykinesia, rigidity, postural instability, and resting tremor. The early phase of PD is characterized by subtle symptoms with a misdiagnosis rate of approximately 16-20%. The difficulty in recognizing early PD has implications for the potential use of novel therapeutic approaches. For this reason, it is important to discover PD brain biomarkers that can indicate early dopaminergic dysfunction through their changes in body fluids, such as saliva, urine, blood, or cerebrospinal fluid (CSF). For the CFS-based test, the invasiveness of sampling is a major limitation, whereas the other body fluids are easier to obtain and could also allow population screening. Following the identification of the crucial role of alpha-synuclein (α-syn) in the pathology of PD, a very large number of studies have summarized its changes in body fluids. However, methodological problems have led to the poor diagnostic/prognostic value of this protein and alternative biomarkers are currently being investigated. The aim of this paper is therefore to summarize studies on protein biomarkers that are alternatives to α-syn, particularly those that change in nigrostriatal areas and in biofluids, with a focus on blood, and, eventually, saliva and urine.

Topics: alpha-Synuclein; Biomarkers; Body Fluids; Brain; Humans; Neurodegenerative Diseases; Parkinson Disease

There are currently no pharmacological treatments available that completely halt or reverse the progression of Parkinson's Disease (PD). Hence, there is an unmet need for neuroprotective therapies. Lewy bodies are a neuropathological hallmark of PD and contain aggregated α-synuclein (α-syn) which is thought to be neurotoxic and therefore a suitable target for therapeutic interventions. To investigate this further, a systematic review was undertaken to evaluate whether anti-α-syn therapies are effective at preventing PD progression in preclinical in vivo models of PD and via current human clinical trials. An electronic literature search was performed using MEDLINE and EMBASE (Ovid), PubMed, the Web of Science Core Collection, and Cochrane databases to collate clinical evidence that investigated the targeting of α-syn. Novel preclinical anti-α-syn therapeutics provided a significant reduction of α-syn aggregations. Biochemical and immunohistochemical analysis of rodent brain tissue demonstrated that treatments reduced α-syn-associated pathology and rescued dopaminergic neuronal loss. Some of the clinical studies did not provide endpoints since they had not yet been completed or were terminated before completion. Completed clinical trials displayed significant tolerability and efficacy at reducing α-syn in patients with PD with minimal adverse effects. Collectively, this review highlights the capacity of anti-α-syn therapies to reduce the accumulation of α-syn in both preclinical and clinical trials. Hence, there is potential and optimism to target α-syn with further clinical trials to restrict dopaminergic neuronal loss and PD progression and/or provide prophylactic protection to avoid the onset of α-syn-induced PD.

Topics: alpha-Synuclein; Brain; Disease Progression; Humans; Lewy Bodies; Parkinson Disease

Parkinson's disease (PD) biomarkers are needed by both clinicians and researchers (for diagnosis, identifying study populations, and monitoring therapeutic response). Imaging, genetic, and biochemical biomarkers have been widely studied. In recent years, extracellular vesicles (EVs) have become a promising material for biomarker development. Proteins and molecular material from any organ, including the central nervous system, can be packed into EVs and transported to the periphery into easily obtainable biological specimens like blood, urine, and saliva. We performed a systematic review and meta-analysis of articles (published before November 15, 2022) reporting biomarker assessment in EVs in PD patients and healthy controls (HCs). Biomarkers were analyzed using random effects meta-analysis and the calculated standardized mean difference (Std.MD). Several proteins and ribonucleic acids have been identified in EVs in PD patients, but only α-synuclein (aSyn) and leucine-rich repeat kinase 2 (LRRK2) were reported in sufficient studies (n = 24 and 6, respectively) to perform a meta-analysis. EV aSyn was significantly increased in neuronal L1 cell adhesion molecule (L1CAM)-positive blood EVs in PD patients compared to HCs (Std.MD = 1.84, 95% confidence interval = 0.76-2.93, P = 0.0009). Further analysis of the biological sample and EV isolation method indicated that L1CAM-IP (immunoprecipitation) directly from plasma was the best isolation method for assessing aSyn in PD patients. Upcoming neuroprotective clinical trials immediately need peripheral biomarkers for identifying individuals at risk of developing PD. Overall, the improved sensitivity of assays means they can identify biomarkers in blood that reflect changes in the brain. CNS-derived EVs in blood will likely play a major role in biomarker development in the coming years. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Biomarkers; Extracellular Vesicles; Humans; Neural Cell Adhesion Molecule L1; Parkinson Disease; Sexually Transmitted Diseases

Parkinson's disease (PD), the most common neurological motor system disorder, which characterised by the irreversible loss of dopaminergic neurones in the substantia nigra pars compacta, and leads to the deficiency of dopamine in the striatum. Deposited Lewy bodies (LBs) in diseased neurones and nerve terminals are the pathological hallmark of PD, and alpha-synuclein (α-Syn) is the most prominent protein in LBs. The tight association between α-Syn and the molecular pathology of PD has generatly increaed the interest in using the α-Syn species as biomarkers to diagnose early PD. α-Syn is not confined to the central nervous system, it is also present in the peripheral tissues, such as human skin. The assessment of skin α-Syn has the potential to be a diagnostic method that not only has excellent sensitivity, specificity, and reproducibility, but also convenient and acceptable to patients. In this review, we (i) integrate the biochemical, aggregation and structural features of α-Syn; (ii) map the distribution of the α-Syn species present in the brain, biological fluids, and peripheral tissues; and (iii) present a critical and comparative analysis of previous studies that have measured α-Syn in the skin. Finally, we provide an outlook on the future of skin biopsy as a diagnostic approach for PD, and highlight its potential implications for clinical trials, clinical decision-making, treatment strategies as well as the development of new therapies.

Topics: alpha-Synuclein; Biomarkers; Humans; Lewy Bodies; Parkinson Disease; Reproducibility of Results

Topics: alpha-Synuclein; Amyloid beta-Peptides; Antibodies, Monoclonal; Brain; Drug Inverse Agonism; Histamine; Humans; Nanoparticle Drug Delivery System; Parkinson Disease; Receptors, Histamine H3; Receptors, Histamine H4

dl-3-n-butylphthalide (dl-NBP) is one of the potent antioxidant compounds that induces profound neuroprotection in stroke and traumatic brain injury. Our previous studies show that dl-NBP reduces brain pathology in Parkinson's disease (PD) following its nanowired delivery together with mesenchymal stem cells (MSCs) exacerbated by concussive head injury (CHI). CHI alone elevates alpha synuclein (ASNC) in brain or cerebrospinal fluid (CSF) associated with elevated TAR DNA-binding protein 43 (TDP-43). TDP-43 protein is also responsible for the pathologies of PD. Thus, it is likely that exacerbation of brain pathology in PD following brain injury may be thwarted using nanowired delivery of monoclonal antibodies (mAb) to ASNC and/or TDP-43. In this review, the co-administration of dl-NBP with MSCs and mAb to ASNC and/or TDP-43 using nanowired delivery in PD and CHI-induced brain pathology is discussed based on our own investigations. Our observations show that co-administration of TiO

Topics: alpha-Synuclein; Antibodies, Monoclonal; Brain Injuries, Traumatic; DNA-Binding Proteins; Humans; Mesenchymal Stem Cells; Nanowires; Neuroprotection; Neuroprotective Agents; Parkinson Disease

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by elevated motor behaviors and dream enactments in REM sleep, often preceding the diagnosis of Parkinson's disease (PD). As RBD could serve as a biomarker for early PD developments, pharmacological interventions targeting α-synuclein aggregation triggered RBD could be applied toward early PD progression. However, robust therapeutic guidelines toward PD-induced RBD are lacking, owing in part to a historical paucity of effective treatments and trials. We reviewed the bidirectional links between α-synuclein neurodegeneration, progressive sleep disorders, and RBD. We highlighted the correlation between RBD development, α-synuclein aggregation, and neuronal apoptosis in key brainstem regions involved in REM sleep atonia maintenance. The current pharmacological intervention strategies targeting RBD and their effects on progressive PD are discussed, as well as current treatments for progressive neurodegeneration and their effects on RBD. We also evaluated emerging and potential pharmacological solutions to sleep disorders and developing synucleinopathies. This review provides insights into the mechanisms and therapeutic targets underlying RBD and PD, and explores bidirectional treatment effects for both diseases, underscoring the need for further research in this area.

Topics: alpha-Synuclein; Humans; Parkinson Disease; REM Sleep Behavior Disorder; Sleep; Sleep Wake Disorders

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, resulting in dopamine depletion and motor behavior deficits. Since the discovery of L-DOPA, it has been the most prescribed drug for symptomatic relief in PD, whose prolonged use, however, causes undesirable motor fluctuations like dyskinesia and dystonia. Further, therapeutics targeting the pathological hallmarks of PD including α-synuclein aggregation, oxidative stress, neuroinflammation, and autophagy impairment have also been developed, yet PD treatment is a largely unmet success. The inception of the nanovesicle-based drug delivery approach over the past few decades brings add-on advantages to the therapeutic strategies for PD treatment in which nanovesicles (basically phospholipid-containing artificial structures) are used to load and deliver drugs to the target site of the body. The present review narrates the characteristic features of nanovesicles including their blood-brain barrier permeability and ability to reach dopaminergic neurons of the brain and finally discusses the current status of this technology in the treatment of PD. From the review, it becomes evident that with the assistance of nanovesicle technology, the therapeutic efficacy of anti-PD pharmaceuticals, phyto-compounds, as well as that of nucleic acids targeting α-synuclein aggregation gained a significant increment. Furthermore, owing to the multiple drug-carrying abilities of nanovesicles, combination therapy targeting multiple pathogenic events of PD has also found success in preclinical studies and will plausibly lead to effective treatment strategies in the near future.

Topics: alpha-Synuclein; Brain; Dopamine; Dopaminergic Neurons; Humans; Levodopa; Parkinson Disease

Inflammatory mechanisms are increasingly recognized as important contributors to the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Our objectives were to, firstly, review inflammation investigation methods in LBD (dementia with Lewy bodies and Parkinson's disease dementia) and, secondly, identify alterations in inflammatory signals in LBD compared to people without neurodegenerative disease and other neurodegenerative diseases. A systematic scoping review was performed by searching major electronic databases (MEDLINE, Embase, Web of Science, and PSYCHInfo) to identify relevant human studies. Of the 2509 results screened, 80 studies were included. Thirty-six studies analyzed postmortem brain tissue, and 44 investigated living subjects with cerebrospinal fluid, blood, and/or brain imaging assessments. Largely cross-sectional data were available, although two longitudinal clinical studies investigated prodromal Lewy body disease. Investigations were focused on inflammatory immune cell activity (microglia, astrocytes, and lymphocytes) and inflammatory molecules (cytokines, etc.). Results of the included studies identified innate and adaptive immune system contributions to inflammation associated with Lewy body pathology and clinical disease features. Different signals in early and late-stage disease, with possible late immune senescence and dystrophic glial cell populations, were identified. The strength of these associations is limited by the varying methodologies, small study sizes, and cross-sectional nature of the data. Longitudinal studies investigating associations with clinical and other biomarker outcomes are needed to improve understanding of inflammatory activity over the course of LBD. This could identify markers of disease activity and support therapeutic development.

Topics: alpha-Synuclein; Cross-Sectional Studies; Dementia; Humans; Inflammation; Lewy Body Disease; Neurodegenerative Diseases; Parkinson Disease

Like many neurodegenerative diseases, Parkinson's disease (PD) is characterized by the formation of proteinaceous aggregates in brain cells. In PD, those proteinaceous aggregates are formed by the α-synuclein (αSyn) and are considered the trademark of this neurodegenerative disease. In addition to PD, αSyn pathological aggregation is also detected in atypical Parkinsonism, including Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), as well as neurodegeneration with brain iron accumulation, some cases of traumatic brain injuries, and variants of Alzheimer's disease. Collectively, these (and other) disorders are referred to as synucleinopathies, highlighting the relation between disease type and protein misfolding/aggregation. Despite these pathological relationships, however, synucleinopathies cover a wide range of pathologies, present with a multiplicity of symptoms, and arise from dysfunctions in different neuroanatomical regions and cell populations. Strikingly, αSyn deposition occurs in different types of cells, with oligodendrocytes being mainly affected in MSA, while aggregates are found in neurons in PD. If multiple factors contribute to the development of a pathology, especially in the cases of slow-developing neurodegenerative disorders, the common presence of αSyn aggregation, as both a marker and potential driver of disease, is puzzling. In this review, we will focus on comparing PD, DLB, and MSA, from symptomatology to molecular description, highlighting the role and contribution of αSyn aggregates in each disorder. We will particularly present recent evidence for the involvement of conformational strains of αSyn aggregates and discuss the reciprocal relationship between αSyn strains and the cellular milieu. Moreover, we will highlight the need for effective methodologies for the strainotyping of aggregates to ameliorate diagnosing capabilities and therapeutic treatments.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Protein Aggregates; Synucleinopathies

Alpha-synuclein seed amplification assays (α-syn SAAs) are promising diagnostic methods for Parkinson's disease (PD) and other synucleinopathies. However, there is limited consensus regarding the diagnostic and differential diagnostic performance of α-syn SAAs on biofluids and peripheral tissues.. A comprehensive research was performed in PubMed, Web of Science, Embase and Cochrane Library. Meta-analysis was performed using a random-effects model. A network meta-analysis based on an ANOVA model was conducted to compare the relative accuracy of α-syn SAAs with different specimens.. The pooled sensitivity and specificity of α-syn SAAs in distinguishing PD from healthy controls or non-neurodegenerative neurological controls were 0.91 (95% confidence interval [CI] 0.89-0.92) and 0.95 (95% CI 0.94-0.96) for cerebrospinal fluid (CSF); 0.91 (95% CI 0.86-0.94) and 0.92 (95% CI 0.87-0.95) for skin; 0.80 (95% CI 0.66-0.89) and 0.87 (95% CI 0.69-0.96) for submandibular gland; 0.44 (95% CI 0.30-0.59) and 0.92 (95% CI 0.79-0.98) for gastrointestinal tract; 0.79 (95% CI 0.70-0.86) and 0.88 (95% CI 0.77-0.95) for saliva; and 0.51 (95% CI 0.39-0.62) and 0.91 (95% CI 0.84-0.96) for olfactory mucosa (OM). The pooled sensitivity and specificity were 0.91 (95% CI 0.89-0.93) and 0.50 (95% CI 0.44-0.55) for CSF, 0.92 (95% CI 0.83-0.97) and 0.22 (95% CI 0.06-0.48) for skin, and 0.55 (95% CI 0.42-0.68) and 0.50 (95% CI 0.35-0.65) for OM in distinguishing PD from multiple system atrophy. The pooled sensitivity and specificity were 0.92 (95% CI 0.89-0.94) and 0.84 (95% CI 0.73-0.91) for CSF, 0.92 (95% CI 0.83-0.97) and 0.88 (95% CI 0.64-0.99) for skin and 0.63 (95% CI 0.52-0.73) and 0.86 (95% CI 0.64-0.97) for OM in distinguishing PD from progressive supranuclear palsy. The pooled sensitivity and specificity were 0.94 (95% CI 0.90-0.97) and 0.95 (95% CI 0.77-1.00) for CSF and 0.94 (95% CI 0.84-0.99) and 0.86 (95% CI 0.42-1.00) for skin in distinguishing PD from corticobasal degeneration.. α-Synuclein SAAs of CSF, skin, saliva, submandibular gland, gastrointestinal tract and OM are promising diagnostic assays for PD, with CSF and skin α-syn SAAs demonstrating higher diagnostic performance.

Topics: alpha-Synuclein; Biomarkers; Humans; Multiple System Atrophy; Network Meta-Analysis; Parkinson Disease

Topics: alpha-Synuclein; Biomarkers; Extracellular Vesicles; Humans; Parkinson Disease

Alpha-synucleinopathies (α-synucleinopathies) such as Parkinson's disease (PD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are all characterized by aggregates of alpha-synuclein (α-syn), but display heterogeneous clinical and pathological phenotypes. The mechanism underlying this heterogeneity is thought to be due to diversity in the α-syn strains present across the diseases. α-syn obtained from the post-mortem brain of patients who lived with these conditions is heterogenous, and displays a different protease sensitivity, ultrastructure, cytotoxicity, and seeding potential. The primary aim of this review is to summarize previous studies investigating these concepts, which not only reflect the idea of different syn strains being present, but demonstrate that each property explains a small part of a much larger puzzle. Strains of α-syn appear at the center of the correlation between α-syn properties and the disease phenotype, likely influenced by external factors. There are considerable similarities in the properties of disease-specific α-syn strains, but MSA seems to consistently display more aggressive traits. Elucidating the molecular underpinnings of heterogeneity amongst α-synucleinopathies holds promise for future clinical translation, allowing for the development of personalized medicine approaches tackling the root cause of each α-synucleinopathy.

Topics: alpha-Synuclein; Dementia; Humans; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

The alteration and aggregation of alpha-synuclein (α-syn) play a crucial role in neurodegenerative diseases collectively termed as synucleinopathies, including Parkinson's disease (PD). The bidirectional interaction of α-syn with lipids and biomembranes impacts not only α-syn aggregation but also lipid homeostasis. Indeed, lipid composition and metabolism are severely perturbed in PD. One explanation for lipid-associated alterations may involve structural changes in α-syn, caused, for example, by missense mutations in the lipid-binding region of α-syn as well as post-translational modifications such as phosphorylation, acetylation, nitration, ubiquitination, truncation, glycosylation, and glycation. Notably, different strategies targeting the α-syn-lipid interaction have been identified and are able to reduce α-syn pathology. These approaches include the modulation of post-translational modifications aiming to reduce the aggregation of α-syn and modify its binding properties to lipid membranes. Furthermore, targeting enzymes involved in various steps of lipid metabolism and exploring the neuroprotective potential of lipids themselves have emerged as novel therapeutic approaches. Taken together, this review focuses on the bidirectional crosstalk of α-syn and lipids and how alterations of this interaction affect PD and thereby open a window for therapeutic interventions.

Topics: alpha-Synuclein; Central Nervous System; Humans; Lipids; Parkinson Disease; Synucleinopathies

A proteostasis network represents a sophisticated cellular system that controls the whole process which leads to properly folded functional proteins. The imbalance of proteostasis determines a quantitative increase in misfolded proteins prone to aggregation and elicits the onset of different diseases. Among these, Parkinson's Disease (PD) is a progressive brain disorder characterized by motor and non-motor signs. In PD pathogenesis, alpha-Synuclein (α-Syn) loses its native structure, triggering a polymerization cascade that leads to the formation of toxic inclusions, the PD hallmark. Because molecular chaperones represent a "cellular arsenal" to counteract protein misfolding and aggregation, the modulation of their expression represents a compelling PD therapeutic strategy. This review will discuss evidence concerning the effects of natural and synthetic small molecules in counteracting α-Syn aggregation process and related toxicity, in different in vitro and in vivo PD models. Firstly, the role of small molecules that modulate the function(s) of chaperones will be highlighted. Then, attention will be paid to small molecules that interfere with different steps of the protein-aggregation process. This overview would stimulate in-depth research on already-known small molecules or the development of new ones, with the aim of developing drugs that are able to modify the progression of the disease.

Topics: alpha-Synuclein; Brain; Humans; Inclusion Bodies; Parkinson Disease; Polymerization

Parkinson's Disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN), leading to motor and non-motor symptoms. While the exact mechanisms remain complex and multifaceted, several molecular pathways have been implicated in PD pathology, including accumulation of misfolded proteins, impaired mitochondrial function, oxidative stress, inflammation, elevated iron levels, etc. Overall, PD's molecular mechanisms involve a complex interplay between genetic, environmental, and cellular factors that disrupt cellular homeostasis, and ultimately lead to the degeneration of dopaminergic neurons. Recently, emerging evidence highlights ferroptosis, an iron-dependent non-apoptotic cell death process, as a pivotal player in the advancement of PD. Notably, oligomeric α-synuclein (α-syn) generates reactive oxygen species (ROS) and lipid peroxides within cellular membranes, potentially triggering ferroptosis. The loss of dopamine, a hallmark of PD, could predispose neurons to ferroptotic vulnerability. This unique form of cell demise unveils fresh insights into PD pathogenesis, necessitating an exploration of the molecular intricacies connecting ferroptosis and PD progression. In this review, the molecular and regulatory mechanisms of ferroptosis and their connection with the pathological processes of PD have been systematically summarized. Furthermore, the features of ferroptosis in PD animal models and clinical trials targeting ferroptosis as a therapeutic approach in PD patients' management are scrutinized.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Ferroptosis; Humans; Iron; Oxidative Stress; Parkinson Disease; Substantia Nigra

Parkinson's disease (PD) is caused due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) which leads to the depletion of dopamine in the body. The lack of dopamine is mainly due to aggregation of misfolded α-synuclein which causes motor impairment in PD. Dopamine is also required for normal retinal function and the light-dark vision cycle. Misfolded α-synuclein present in inner retinal layers causes vision-associated problems in PD patients. Hence, individuals with PD also experience structural and functional changes in the retina. Mutation in LRRK2, PARK2, PARK7, PINK1, or SNCA genes and mitochondria dysfunction also play a role in the pathophysiology of PD. In this review, we discussed the different etiologies which lead to PD and future prospects of employing non-invasive techniques and retinal changes to diagnose the onset of PD earlier.

Topics: alpha-Synuclein; Dopamine; Dopaminergic Neurons; Early Diagnosis; Humans; Parkinson Disease; Retina; Substantia Nigra

Parkinson's disease (PD) is an aging-associated neurodegenerative disorder with the hallmark of abnormal aggregates of alpha-synuclein (α-syn) in Lewy bodies (LBs) and Lewy neurites (LNs). Currently, pathogenic α-syn and mitochondrial dysfunction have been considered as prominent roles that give impetus to the PD onset. This review describes the α-syn pathology and mitochondrial alterations in PD, and focuses on how α-syn interacts with multiple aspects of mitochondrial homeostasis in the pathogenesis of PD.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Mitochondria; Neurodegenerative Diseases; Parkinson Disease

α-Synuclein is a member of a protein of synucleins, which is a presynaptic neuron protein. It is usually highly expressed in the brain and participates in the formation and transmission of nerve synapses. It has been reported that abnormal aggregation of α-Syn can induce the activation of NLRP3 inflammasome in microglia, increase the production of IL-1β, and aggravate neuroinflammation. Therefore, it is recognized as one of the important factors leading to neuroinflammation in Parkinson's disease. In this paper, we aimed to explore the influence of post-translational modification of α-Syn on its pathological aggregation and summarize various pathways that activate NLRP3 triggered by α-Syn and targeted therapeutic strategies, which provided new insights for further exploring the origin and targeted therapy of Parkinson's disease.

Topics: alpha-Synuclein; Humans; Inflammasomes; Microglia; Neuroinflammatory Diseases; NLR Family, Pyrin Domain-Containing 3 Protein; Parkinson Disease

Parkinson's disease (PD) is a devastating disease associated with accumulation of α-synuclein (α-Syn) within dopaminergic neurons, leading to neuronal death. PD is characterized by both motor and non-motor clinical symptoms. Several studies indicate that autophagy, an important intracellular degradation pathway, may be involved in different neurodegenerative diseases including PD. The autophagic process mediates the degradation of protein aggregates, damaged and unneeded proteins, and organelles, allowing their clearance, and thereby maintaining cell homeostasis. Impaired autophagy may cause the accumulation of abnormal proteins. Incomplete or impaired autophagy may explain the neurotoxic accumulation of protein aggregates in several neurodegenerative diseases including PD. Indeed, studies have suggested the contribution of impaired autophagy to α-Syn accumulation, the death of dopaminergic neurons, and neuroinflammation. In this review, we summarize the recent literature on the involvement of autophagy in PD pathogenesis.

Topics: alpha-Synuclein; Autophagy; Dopaminergic Neurons; Humans; Parkinson Disease; Protein Aggregates

The small neuronal protein α-synuclein (αS) is found in pre-synaptic terminals and plays a role in vesicle recycling and neurotransmission. Fibrillar aggregates of αS are the hallmark of Parkinson's disease and related neurodegenerative disorders. In both health and disease, interactions with lipids influence αS's structure and function, prompting much study of the effects of lipids on αS aggregation. A comprehensive collection (126 examples) of aggregation rate data for various αS/lipid combinations was presented, including combinations of lipid variations and mutations or post-translational modifications of αS. These data were interpreted in terms of lipid structure to identify general trends. These tabulated data serve as a resource for the community to help in the interpretation of aggregation experiments with lipids and to be potentially used as inputs for computational models of lipid effects on aggregation.

Topics: alpha-Synuclein; Humans; Lipids; Neurodegenerative Diseases; Parkinson Disease

Dopaminergic neurons are constantly threatened by the thin boundaries between functional α-synuclein (AS) structural disorder and pathogenic aggregation, and between dopamine (DA) neurotransmitter activity and accumulation of cytotoxic by-products. The possibilities of developing drugs for Parkinson's disease (PD) depend on our understanding of the molecular mechanisms that cause or accompany the pathological structural changes in AS. This review focuses on the three interconnected aspects of AS conformational transitions, its aggregation pathways and ligand binding. Specifically, the interactions of AS with DA, DA metabolites, DA analogs and DA agonists are considered. Recent advances in the field are discussed with reference to the structural properties of AS and the methodologies employed. Although several issues are still object of debate, salient structural features of the protein, the aggregates and the ligands can be identified, in the hope of fueling experimental and computational approaches to the discovery of novel disease-modifying agents.

Topics: alpha-Synuclein; Dopamine; Dopaminergic Neurons; Humans; Molecular Conformation; Parkinson Disease

Peptides and their mimetics are increasingly recognised as drug-like molecules, particularly for intracellular protein-protein interactions too large for inhibition by small molecules, and inaccessible to larger biologics. In the past two decades, evidence associating the misfolding and aggregation of alpha-synuclein strongly implicates this protein in disease onset and progression of Parkinson's disease and related synucleinopathies. The subsequent formation of toxic, intracellular, Lewy body deposits, in which alpha-synuclein is a major component, is a key diagnostic hallmark of the disease. To reach their therapeutic site of action, peptides must both cross the blood-brain barrier and enter dopaminergic neurons to prevent the formation of these intracellular inclusions. In this review, we describe and summarise the current efforts made in the development of peptides and their mimetics to directly engage with alpha-synuclein with the intention of modulating aggregation, and importantly, toxicity. This is a rapidly expanding field with great socioeconomic impact; these molecules harbour significant promise as therapeutics, or as early biomarkers during prodromal disease stages, or both. As these are age-dependent conditions, an increasing global life expectancy means disease prevalence is rising. No current treatments exist to either prevent or slow disease progression. It is therefore crucial that drugs are developed for these conditions before health care and social care capacities become overrun.

Topics: alpha-Synuclein; Humans; Inclusion Bodies; Parkinson Disease; Peptides; Synucleinopathies

Lewy bodies that contain aggregated α-synuclein in dopamine neurons are the main culprit for neurodegeneration in Parkinson's disease. However, mitochondrial dysfunction has a well-established and prominent role in the pathogenesis of Parkinson's disease. The exact mechanism by which α-synuclein causes dopamine neuronal loss is unclear. Recent evidence suggests that aggregated α-synuclein localises in the mitochondria contributes to oxidative stress-mediated apoptosis in neurons. Therefore, the involvement of aggregated α-synuclein in mitochondrial dysfunction-mediated neuronal loss has made it an emerging drug target for the treatment of Parkinson's disease. However, the exact mechanism by which α-synuclein permeabilises through the mitochondrial membrane and affects the electron transport chain remains under investigation. In the present study, we describe mitochondria-α-synuclein interactions and how α-synuclein aggregation modulates mitochondrial homeostasis in Parkinson's disease pathogenesis. We also discuss recent therapeutic interventions targeting α-synuclein aggregation that may help researchers to design novel therapeutic treatments for Parkinson's disease.

Topics: alpha-Synuclein; Apoptosis; Dopaminergic Neurons; Humans; Lewy Bodies; Mitochondria; Mitochondrial Diseases; Oxidative Stress; Parkinson Disease; Protein Aggregation, Pathological

The spreading of misfolded alpha-synuclein (α-syn) protein has been observed in animal models of Parkinson's disease (PD) and other α-synucleinopathies that mimic human PD pathologies. In animal models, the spreading of α-syn has been associated with motor dysfunction and neuronal death. However, variability in both susceptible brain regions and cellular populations limits our understanding of the consequences of α-syn spreading and the development of associated therapies. Here, we have reviewed the physiological and pathological functions of α-syn and summarized the susceptible brain regions and cell types identified from human postmortem studies and exogenous α-syn injection-based animal models. We have reviewed the methods for inducing α-syn aggregation, the specific hosts, the inoculation sites, the routes of propagation, and other experimental settings that may affect the spreading pattern of α-syn, as reported in current studies. Understanding the spread of α-syn to produce a consistent PD animal model is vital for future drug discovery.

Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Parkinson Disease; Synucleinopathies

Parkinson's disease is the second most prevalent neurodegenerative disease. The loss of dopaminergic neurons in the substantia nigra is one of the pathological hallmarks of PD. PD also belongs to the class of neurodegenerative disease known as 'Synucleinopathies' as α-synuclein is responsible for disease development. The presence of aggregated α-synuclein associated with other proteins found in the Lewy bodies and Lewy neurites in the substantia nigra and other regions of the brain including locus ceruleus, dorsal vagal nucleus, nucleus basalis of Meynert and cerebral cortex is one of the central events for PD development. The complete biological function of α-synuclein is still debated. Besides its ability to propagate, it undergoes various post-translational modifications which play a paramount role in PD development and progression. Also, the aggregation of α-synuclein is modulated by various post-translational modifications. Here, we present a summary of multiple PTMs involved in the modulation of α-synuclein directly or indirectly and to identify their neuroprotective or neurotoxic roles, which might act as potential therapeutic targets for Parkinson's disease.

Topics: alpha-Synuclein; Brain; Dopaminergic Neurons; Humans; Lewy Bodies; Neuroprotective Agents; Neurotoxins; Parkinson Disease; Protein Aggregation, Pathological; Protein Processing, Post-Translational

Parkinson's disease is characterized by typical motor symptoms, loss of dopamine neurons in the substantia nigra, and accumulation of Lewy body composed of mutated α-synuclein. However, now it is considered as a generalized disease with multiple pathological features. Present available treatments can ameliorate symptoms at least for a while, but only a few therapies could delay progressive neurodegeneration of dopamine neurons. Lewy body accumulates in peripheral tissues many years before motor dysfunction becomes manifest, suggesting that disease-modifying therapy should start earlier during the premotor stage. Long-termed regulation of lifestyle, diet and supplement of nutraceuticals may be possible ways for the disease-modification. Diet can reduce the incidence of Parkinson's disease and phytochemicals, major bioactive ingredients of herbs and plant food, modulate multiple pathogenic factors and exert neuroprotective effects in preclinical studies. This review presents mechanisms underlying neuroprotection of phytochemicals against neuronal cell death and α-synuclein toxicity in Parkinson's disease. Phytochemicals are antioxidants, maintain mitochondrial function and homeostasis, prevent intrinsic apoptosis and neuroinflammation, activate cellular signal pathways to induce anti-apoptotic and pro-survival genes, such as Bcl-2 protein family and neurotrophic factors, and promote cleavage of damaged mitochondria and α-synuclein aggregates. Phytochemicals prevent α-synuclein oligomerization and aggregation, and dissolve preformed α-synuclein aggregates. Novel neuroprotective agents are expected to develop based on the scaffold of phytochemicals permeable across the blood-brain-barrier, to increase the bioavailability, ameliorate brain dysfunction and prevent neurodegeneration.

Topics: alpha-Synuclein; Humans; Neuroprotective Agents; Parkinson Disease; Phytochemicals; Substantia Nigra; Virulence Factors

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is defined pathologically by the abnormal accumulation of the presynaptic protein alpha-synuclein (aSyn) in the form of Lewy bodies and Lewy neurites and loss of midbrain dopaminergic neurons in the substantia nigra pars compacta. Because of aSyn's involvement in both sporadic and familial forms of PD, it has become a key target for the development of novel therapeutics. Aberrant aSyn is associated with multiple mechanisms of neuronal dysfunction and degeneration including inflammation, impaired mitochondrial function, altered protein degradation systems, and oxidative stress. Inflammation, in particular, has emerged as a potential significant contributor early in the disease making it an attractive target for disease modification and neuroprotection. Thus, immunotherapies targeting aSyn are currently being investigated in pre-clinical and clinical trials. The focus of this review is to highlight the role of aSyn in neuroinflammation and discuss the current status of aSyn-directed immunotherapies in pre-clinical and clinical trials for PD.

Topics: alpha-Synuclein; Animals; Clinical Trials as Topic; Dopaminergic Neurons; Humans; Immune System; Immunotherapy; Immunotherapy, Active; Lewy Bodies; Mice, Transgenic; Molecular Targeted Therapy; Neuroinflammatory Diseases; Oxidative Stress; Parkinson Disease; Substantia Nigra

The aggregation of alpha-synuclein (α-Syn) plays a critical role in the development of Parkinson's disease (PD) and other synucleinopathies. α-Syn, which is encoded by the SNCA gene, is a lysine-rich soluble amphipathic protein normally expressed in neurons. Located in the cytosolic domain, this protein has the ability to remodel itself in plasma membranes, where it assumes an alpha-helix conformation. However, the protein can also adopt another conformation rich in cross-beta sheets, undergoing mutations and post-translational modifications, then leading the protein to an unusual aggregation in the form of Lewy bodies (LB), which are cytoplasmic inclusions constituted predominantly by α-Syn. Pathogenic mechanisms affecting the structural and functional stability of α-Syn - such as endoplasmic reticulum stress, Golgi complex fragmentation, disfunctional protein degradation systems, aberrant interactions with mitochondrial membranes and nuclear DNA, altered cytoskeleton dynamics, disrupted neuronal plasmatic membrane, dysfunctional vesicular transport, and formation of extracellular toxic aggregates - contribute all to the pathogenic progression of PD and synucleinopathies. In this review, we describe the collective knowledge on this topic and provide an update on the critical role of α-Syn aggregates, both at the cellular and molecular levels, in the deregulation of organelles affecting the cellular homeostasis and leading to neuronal cell death in PD and other synucleinopathies.

Topics: alpha-Synuclein; Animals; Brain; Humans; Neurons; Parkinson Disease; Synucleinopathies

Parkinson's disease (PD) is a neurodegenerative disorder that affects over 10 million aging people worldwide. This condition is characterized by the degeneration of dopaminergic neurons in the pars compacta region of the substantia nigra (SNpc) and by aggregation of proteins, commonly α-synuclein (SNCA). The formation of Lewy bodies that encapsulate aggregated proteins in lipid vesicles is a hallmark of PD. Glycosylation of proteins and neuroinflammation are involved in the pathogenesis. SNCA has many posttranslational modifications and interacts with components of membranes that affect aggregation. The large membrane lipid dolichol accumulates in the brain upon age and has a significant effect on membrane structure. The replacement of dopamine and dopaminergic neurons are at the forefront of therapeutic development. This review examines the role of membrane lipids, glycolipids, glycoproteins and dopamine in the aggregation of SNCA and development of PD. We discuss the SNCA-dopamine-neuromelanin-dolichol axis and the role of membranes in neuronal stem cells that could be a regenerative therapy for PD patients.

Topics: alpha-Synuclein; Dopaminergic Neurons; Glycoconjugates; Glycomics; Humans; Parkinson Disease; Substantia Nigra

Alpha-synuclein deposits, the pathological hallmarks of Parkinson's disease, are consistently found in the gastrointestinal tract of parkinsonian subjects. These observations have raised the potential that endoscopically obtainable mucosal biopsies can aid to a molecular diagnosis of the disease. The possible usefulness of mucosal biopsies is, however, not limited to the detection of alpha-synuclein, but also extends to other essential aspects underlying pathophysiological mechanisms of gastrointestinal manifestations in Parkinson's disease. The aim of the current review is to provide an appraisal of the existing studies showing that gastrointestinal biopsies can be used for the analysis of enteric neuronal and glial cell morphology, intestinal epithelial barrier function, and gastrointestinal inflammation in Parkinson's disease. A perspective on the generation of organoids with GI biopsies and the potential use of single-cell and spatial transcriptomic technologies will be also addressed.

Topics: alpha-Synuclein; Biopsy; Gastrointestinal Tract; Humans; Neurons; Parkinson Disease

The α-synucleinopathies comprise a group of adult-onset neurodegenerative disorders including Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB,) and - as a restricted non-motor form - pure autonomic failure (PAF). Neuropathologically, the α-synucleinopathies are characterized by aggregates of misfolded α-synuclein in the central and peripheral nervous system. Cardiovascular autonomic failure is a common non-motor symptom in people with PD, a key diagnostic criterion in MSA, a supportive feature for the diagnosis of DLB and disease-defining in PAF. The site of autonomic nervous system lesion differs between the α-synucleinopathies, with a predominantly central lesion pattern in MSA versus a peripheral one in PD, DLB, and PAF. In clinical practice, overlapping autonomic features often challenge the differential diagnosis among the α-synucleinopathies, but also distinguish them from related disorders, such as the tauopathies or other neurodegenerative ataxias. In this review, we discuss the differential diagnostic yield of cardiovascular autonomic failure in individuals presenting with isolated autonomic failure, parkinsonism, cognitive impairment, or cerebellar ataxia.

Topics: alpha-Synuclein; Diagnosis, Differential; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Pure Autonomic Failure; Synucleinopathies

Patients with idiopathic Parkinson's disease develop symptoms of the hallucination-psychosis spectrum in more than 20%. Most common are visual hallucinations. The pathogenesis of hallucinations mainly depends on disease duration, the distribution and extent of alpha-synuclein pathology, and modulating effects of the dopaminergic therapy. When managing PD hallucinations both anti-delirogenic actions and medication management are important. However, decrease in dopaminergic medication may lead to critical worsening of akinesia. If appropriate neuroleptic medication - essentially quetiapin or clozapin - can be considered. Instead, anti-dopaminergic neuroleptics should not be used owing to their pro-akinetic side-effects. Here, we provide therapy recommendations to manage PD hallucinations based on an up-to-date targeted review of the literature and expert-based empirical evidence.. Mehr als 20% der Patienten mit idiopathischem Parkinson-Syndrom (IPS) entwickeln Psychosen. Am häufigsten sind visuelle Halluzinationen. Bei der Entwicklung der Psychosen scheinen die Pathogenese der Parkinson-Erkrankung sowie ihre Dauer ebenso eine Rolle zu spielen wie modulierende Effekte der dopaminergen Therapie. Beim Therapiemanagement steht neben allgemeinen Maßnahmen zunächst die Anpassung der dopaminergen Therapie im Vordergrund. Dies kann zu einer Gratwanderung werden zwischen Besserung der Halluzinationen und Verschlechterung der Motorik. Bei unzureichendem Erfolg kann eine antipsychotische Therapie notwendig werden – dabei ist die Auswahl auf sehr wenige Antipsychotika beschränkt, um nicht ernsthafte motorische Verschlechterungen zu riskieren. In der vorliegenden Arbeit wurden basierend auf dem aktuellen Stand der Literatur sowie empirischen Experten-basierten Erfahrungen aus dem klinischen Alltag relevante Aspekte zu Halluzinationen bei IPS-Patienten in der Praxis zusammengefasst und Empfehlungen zum Therapiemanagement erarbeitet.

Topics: alpha-Synuclein; Antipsychotic Agents; Hallucinations; Humans; Parkinson Disease; Psychotic Disorders

For the last two decades, pathogenic concepts in Parkinson disease (PD) have revolved around the toxicity and spread of α-synuclein. Thus, α-synuclein would follow caudo-rostral propagation from the periphery to the central nervous system, first producing non-motor manifestations (such as constipation, sleep disorders and hyposmia), and subsequently impinging upon the mesencephalon to account for the cardinal motor features before reaching the neocortex as the disease evolves towards dementia. This model is the prevailing theory of the principal neurobiological mechanism of disease. Here, we scrutinize the temporal evolution of motor and non-motor manifestations in PD and suggest that, even though the postulated bottom-up mechanisms are likely to be involved, early involvement of the nigrostriatal system is a key and prominent pathophysiological mechanism. Upcoming studies of detailed clinical manifestations with newer neuroimaging techniques will allow us to more closely define, in vivo, the role of α-synuclein aggregates with respect to neuronal loss during the onset and progression of PD.

Topics: alpha-Synuclein; Animals; Efferent Pathways; Humans; Neural Pathways; Parkinson Disease

Cytoplasmic deposition of aberrantly misfolded α-synuclein (α-Syn) is a common feature of synucleinopathies, including Parkinson's disease (PD). However, the precise pathogenic mechanism of α-Syn in synucleinopathies remains elusive. Emerging evidence has suggested that α-Syn may contribute to PD pathogenesis in several ways; wherein the contribution of fibrillar species, for exerting toxicity and disease transmission, cannot be neglected. Further, the oligomeric species could be the most plausible neurotoxic species causing neuronal cell death. However, understanding the structural and molecular insights of these oligomers are very challenging due to the heterogeneity and transient nature of the species. In this review, we discuss the recent advancements in understanding the formation and role of α-Syn oligomers in PD pathogenesis. We also summarize the different types of α-Syn oligomeric species and potential mechanisms to exert neurotoxicity. Finally, we address the possible ways to target α-Syn as a promising approach against PD and the possible future directions.

Topics: alpha-Synuclein; Humans; Parkinson Disease; Synucleinopathies

Parkinson's disease is the second most common neurological disorder marked by characteristic poverty and dysfunction in movement. There are many mechanisms and factors which have been postulated to be associated with the neurodegenerative pathway(s) resulting in distinctive loss of neurons in the substantia nigra. Subsequently, the neuropathology is more widespread and exhibited in other areas of the brain, and enteric nervous system. Aggregates of misfolded α-synuclein or Lewy bodies are the hallmark of the illness and appear to be central in the whole cascade of cell destruction. There are many processes implicated in neuronal destruction including: oxidative stress, excitotoxicity, mitochondrial dysfunction, an imbalance in protein homeostasis and neuroinflammation. Interesting, inflammation induced by pathogens (including, bacteria and viruses) has been associated in the pathogenesis of the disease. Bacteria such as Helicobacter pylori and Helicobacter suis appear to colonise the gut, and elicit systemic immune responses, which is them transmitted via the gut-axis to the brain, where cytotoxic cytokines induce neuroinflammation and cell death. This conforms to the bottom-top hypothesis proposed by Braak. The gut is also implicated in two other theories postulated in the development and progression of the disorder, namely, the top-down and the threshold. There is a possibility that these theories may be inter-linked and operate together to certain degree. Ultimately specific trigger factors or conditions may govern the occurrences of these processes in genetically predisposed individuals. Nevertheless, the importance of pathogen-related gut infections cannot be overlooked, since it can result in dysbiosis of gut microbes, which may orchestrate α-synuclein pathology and eventually cell destruction.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Neurons; Parkinson Disease; Substantia Nigra

Two hallmarks of Parkinson's disease (PD) are the widespread deposition of misfolded alpha-synuclein (αSyn) protein in the nervous system and loss of substantia nigra dopamine neurons. Recent research has suggested that αSyn aggregates in the enteric nervous system (ENS) lead to prodromal gastrointestinal (GI) symptoms such as constipation in PD, then propagating to the brain stem and eventually triggering neurodegeneration and motor symptoms. Additionally, whether the microbiome changes in PD contribute to the primary pathogenesis or, alternatively, are consequential to either the disease process or medication is still unclear. In this review, we discuss the possible roles of αSyn and microbiome changes in the GI system in PD and consider if and how the changes interact and contribute to the disease process and symptoms.

Topics: alpha-Synuclein; Enteric Nervous System; Gastrointestinal Tract; Humans; Microbiota; Parkinson Disease

Alpha-synuclein aggregates are the hallmark pathology of Parkinson's disease, which can propagate in a stereotypical pattern along the brain-body axis. Parkinson's disease patients not only display heterogeneous symptoms but also show variable patterns of alpha-synuclein pathology and affected neuronal systems during the disease course, complicating early and accurate diagnosis. Emerging data from post-mortem and imaging studies strongly suggest that disease heterogeneity could, at least in part, be explained by variable disease onset site, i.e. brain or body. This has led to the recently hypothesized formulation of two Parkinson's disease-subtypes, a body-first subtype where pathogenic alpha-synuclein arises in the body and spreads to the brain, and a brain-first subtype where pathogenic alpha-synuclein arises in the brain and spreads to the body. From a preclinical perspective, several animal models have been adapted or developed to reproduce Parkinson's disease-like pathology in the brain or periphery aiming to address the site of disease onset. Here, we review the current rodent and primate models that aim to reproduce Parkinson's disease pathology development and spreading in the brain and/or body and discuss the value and shortcomings of these models for the development of potential future applications in clinical trials and personalized medicine.

Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder and the fastest growing neurologic disease in the world, yet no disease-modifying therapy is available for this disabling condition. Multiple lines of evidence implicate the protein

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Neurodegenerative Diseases; Parkinson Disease

Braak's hypothesis has been extremely influential over the last two decades. However, neuropathological and clinical evidence suggest that the model does not conform to all patients with Parkinson's disease (PD). To resolve this controversy, a new model was recently proposed; in brain-first PD, the initial α-synuclein pathology arise inside the central nervous system, likely rostral to the substantia nigra pars compacta, and spread via interconnected structures - eventually affecting the autonomic nervous system; in body-first PD, the initial pathological α-synuclein originates in the enteric nervous system with subsequent caudo-rostral propagation to the autonomic and central nervous system. By using REM-sleep behavior disorder (RBD) as a clinical identifier to distinguish between body-first PD (RBD-positive at motor symptom onset) and brain-first PD (RBD-negative at motor symptom onset), we explored the literature to evaluate clinical and imaging differences between these proposed subtypes. Body-first PD patients display: 1) a larger burden of autonomic symptoms - in particular orthostatic hypotension and constipation, 2) more frequent pathological α-synuclein in peripheral tissues, 3) more brainstem and autonomic nervous system involvement in imaging studies, 4) more symmetric striatal dopaminergic loss and motor symptoms, and 5) slightly more olfactory dysfunction. In contrast, only minor cortical metabolic alterations emerge before motor symptoms in body-first. Brain-first PD is characterized by the opposite clinical and imaging patterns. Patients with pathological LRRK2 genetic variants mostly resemble a brain-first PD profile whereas patients with GBA variants typically conform to a body-first profile. SNCA-variant carriers are equally distributed between both subtypes. Overall, the literature indicates that body-first and brain-first PD might be two distinguishable entities on some clinical and imaging markers.

Topics: alpha-Synuclein; Brain; Humans; Parkinson Disease; REM Sleep Behavior Disorder

Alpha-synuclein (α-synuclein) is a small, acidic protein containing 140 amino acids, highly expressed in the brain and primarily localized in the presynaptic terminals. It is found in high concentrations in Lewy Bodies, proteinaceous aggregates that constitute a typical histopathologic hallmark of Parkinson's disease. Altered environmental conditions, genetic mutations and post-translational changes can trigger abnormal aggregation processes with the increased frequency of oligomers, protofibrils, and fibrils formation that perturbs the neuronal homeostasis leading to cell death. Relevant to neuronal activity, a function of α-synuclein that has been extensively detailed is its regulatory actions in the trafficking of synaptic vesicles, including the processes of exocytosis, endocytosis and neurotransmitter release. Most recently, increasing attention has been paid to the possible role that α-synuclein plays at a postsynaptic level by interacting with selective subunits of the glutamate N-methyl-d-aspartate receptor, altering the corticostriatal plasticity of distinct neuronal populations.

Topics: alpha-Synuclein; Animals; Corpus Striatum; Disease Models, Animal; Humans; Lewy Bodies; Models, Animal; Parkinson Disease

The notion that autoimmune responses to α-synuclein may be involved in the pathogenesis of this disorder stems from reports that mutations in α-synuclein or certain alleles of the major histocompatibility complex (MHC) are associated with the disease and that dopaminergic and norepinephrinergic neurons in the midbrain can present antigenic epitopes. Here, we discuss recent evidence that a defined set of peptides derived from α-synuclein act as antigenic epitopes displayed by specific MHC alleles and drive helper and cytotoxic T cell responses in patients with PD. Moreover, phosphorylated α-synuclein may activate T cell responses in a less restricted manner in PD. While the roles for the acquired immune system in disease pathogenesis remain unknown, preclinical animal models and in vitro studies indicate that T cells may interact with neurons and exert effects related to neuronal death and neuroprotection. These findings suggest that therapeutics that target T cells and ameliorate the incidence or disease severity of inflammatory bowel disorders or CNS autoimmune diseases such as multiple sclerosis may be useful in PD.

Topics: alpha-Synuclein; Animals; Dopamine; Humans; Neurons; Parkinson Disease; T-Lymphocytes

Human Central Nervous System (CNS) is the complex part of the human body, which regulates multiple cellular and molecular events taking place simultaneously. Parkinsons Disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). The pathological hallmarks of PD are loss of dopaminergic neurons in the substantianigra (SN) pars compacta (SNpc) and accumulation of misfolded α-synuclein, in intra-cytoplasmic inclusions called Lewy bodies (LBs). So far, there is no cure for PD, due to the complexities of molecular mechanisms and events taking place during the pathogenesis of PD. Drosophila melanogaster is an appropriate model organism to unravel the pathogenicity not only behind PD but also other NDs. In this context as numerous biological functions are preserved between Drosophila and humans. Apart from sharing 75% of human disease-causing genes homolog in Drosophila, behavioral responses like memory-based tests, negative geotaxis, courtship and mating are also well studied. The genetic, as well as environmental factors, can be studied in Drosophila to understand the geneenvironment interactions behind the disease condition. Through genetic manipulation, mutant flies can be generated harboring human orthologs, which can prove to be an excellent model to understand the effect of the mutant protein on the pathogenicity of NDs.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Drosophila melanogaster; Humans; Lewy Bodies; Parkinson Disease

α-synucleinopathies, encompassing Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are devastating neurodegenerative diseases for which available therapeutic options are scarce, mostly because of our limited understanding of their pathophysiology. Although these pathologies are attributed to an intracellular accumulation of the α-synuclein protein in the nervous system with subsequent neuronal loss, the trigger(s) of this accumulation is/are not clearly identified. Among the existing hypotheses, interest in the hypothesis advocating the involvement of infectious agents in the onset of these diseases is renewed. In this article, we aimed to review the ongoing relevant factors favoring and opposing this hypothesis, focusing on (1) the potential antimicrobial role of α-synuclein, (2) potential entry points of pathogens in regard to early symptoms of diverse α-synucleinopathies, (3) pre-existing literature reviews assessing potential associations between infectious agents and Parkinson's disease, (4) original studies assessing these associations for dementia with Lewy bodies and multiple system atrophy (identified through a systematic literature review), and finally (5) potential susceptibility factors modulating the effects of infectious agents on the nervous system. © 2022 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

α-Synuclein (αS) is a small, unstructured, presynaptic protein expressed in the brain. Its aggregated form is a major component of Lewy bodies, the large proteinaceous deposits in Parkinson's disease. The closely related protein, β-Synuclein (βS), is co-expressed with αS. In vitro, βS acts as a molecular chaperone to inhibit αS aggregation. As a result of this assignation, βS has been largely understudied in comparison to αS. However, recent reports suggest that βS promotes neurotoxicity, implying that βS is involved in other cellular pathways with functions independent of αS. Here, we review the current literature pertaining to human βS in order to understand better the role of βS in homeostasis and pathology. Firstly, the structure of βS is discussed. Secondly, the ability of βS to (i) act as a molecular chaperone; (ii) regulate synaptic function, lipid binding, and the nigrostriatal dopaminergic system; (iii) mediate apoptosis; (iv) participate in protein degradation pathways; (v) modulate intracellular metal levels; and (vi) promote cellular toxicity and protein aggregation is explored. Thirdly, the P123H and V70M mutations of βS, which are associated with dementia with Lewy bodies, are discussed. Finally, the importance of post-translational modifications on the structure and function of βS is reviewed. Overall, it is concluded that βS has both synergistic and antagonistic interactions with αS, but it may also possess important cellular functions independent of αS.

Topics: alpha-Synuclein; beta-Synuclein; Brain; Humans; Lewy Bodies; Parkinson Disease; Protein Aggregates

The vast majority of neurodegenerative diseases are associated with an accumulation of undegraded and aggregated proteins. Hence the word proteinopathies is now used to refer to these neurodegenerative diseases. The synucleinopathies are one component of them, in particular in Parkinson's disease. The neuropathological features of Parkinson's disease are the progressive loss of dopamine neurons in the midbrain and the formation of aggregates composed mainly of a-synuclein protein. Experimental evidence suggests that under pathological conditions, normal soluble a-synuclein protein adopts an abnormal folding and subsequently aggregates, with a propensity to spread throughout the central nervous system. This review article discusses the specifics of a-synuclein aggregation and emerging mechanisms for understanding its spread and aims at providing a molecular explanation for the progression of the disease in humans.. Maladie de Parkinson - Le rôle de la synucléine.. La vaste majorité des maladies neurodégénératives sont associées à une accumulation de protéines non dégradées et agrégées. On appelle ainsi ces maladies, protéinopathies. Les synucléinopathies en sont une des composantes, en particulier la maladie de Parkinson. Les caractéristiques neuropathologiques de la maladie de Parkinson comprennent la perte progressive de neurones dopaminergiques du mésencéphale et la formation d’agrégats protéiques, constitués notamment de la protéine a-synucléine. Des preuves expérimentales suggèrent que dans des conditions pathologiques, cette protéine, normalement soluble, adopte un repliement anormal et s’agrège, avec une propension à se propager dans tout le système nerveux central. Dans cette Synthèse, nous discuterons des spécificités de l’agrégation de l’a-synucléine et de ses mécanismes, qui permettent désormais de comprendre sa propagation et fournissent une explication moléculaire à la progression de la maladie chez l’homme.

Topics: alpha-Synuclein; Dopaminergic Neurons; Humans; Neurodegenerative Diseases; Parkinson Disease

Gaucher disease (GD), one of the most common lysosomal storage diseases, is caused by mutations in the gene, GBA1, that leads to defective glucocerebrosidase activity resulting in the accumulation and storage of glycosphingolipids. However, the pathophysiology of GD is more complicated leading to various associated conditions such as skeletal manifestations and Parkinson's disease (PD). These may result from oxidative stress and inflammatory responses due to complex interconnection of downstream factors such as substrate accumulation, endoplasmic reticulum (ER) stress, unfolded protein response (UPR), calcium dysregulation, mitochondrial dysfunction, defective autophagy, accumulation of α-synuclein aggregates, altered secretion and function of extracellular vesicles (EVs), and immunologic hyperactivity. Here we provide an overview of lysosomal storage diseases followed by a comprehensive review of the factors contributing to oxidative stress and inflammation in GD pathophysiology, mechanisms underlying the possible associated complications, current established treatments for GD, their limitations, and potential primary and adjunctive treatment options targeting these factors.

Topics: alpha-Synuclein; Gaucher Disease; Glucosylceramidase; Humans; Lipids; Lysosomes; Parkinson Disease

The synuclein family includes three neuronal proteins, named α-synuclein, β-synuclein, and γ-synuclein, that have peculiar structural features. α-synuclein is largely known for being a key protein in the pathophysiology of Parkinson's disease (PD) and other synucleinopathies, namely, dementia with Lewy bodies and multisystem atrophy. The role of β-synuclein and γ-synuclein is less well understood in terms of physiological functions and potential contribution to human diseases. α-synuclein has been investigated extensively in both cerebrospinal fluid (CSF) and blood as a potential biomarker for synucleinopathies. Recently, great attention has been also paid to β-synuclein, whose CSF and blood levels seem to reflect synaptic damage and neurodegeneration independent of the presence of synucleinopathy. In this review, we aim to provide an overview on the pathophysiological roles of the synucleins. Because γ-synuclein has been poorly investigated in the field of synucleinopathy and its pathophysiological roles are far from being clear, we focus on the interactions between α-synuclein and β-synuclein in PD. We also discuss the role of α-synuclein and β-synuclein as potential biomarkers to improve the diagnostic characterization of synucleinopathies, thus highlighting their potential application in clinical trials for disease-modifying therapies. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; beta-Synuclein; Biomarkers; gamma-Synuclein; Humans; Parkinson Disease; Synucleinopathies

Parkinson's disease is a progressive neurodegenerative disorder that is characterized by pathological protein inclusions that form in the brains of patients, leading to neuron loss and the observed clinical symptoms. These inclusions, containing aggregates of the protein α-Synuclein, spread throughout the brain as the disease progresses. This spreading follows patterns that inform our understanding of the disease. One way to further our understanding of disease progression is to model the discrete steps from when a cell first encounters an aggregate to when those aggregates propagate to new cells. This review will serve to highlight the recent progress made in the effort to better understand the mechanistic steps that determine how this propagation happens at the cellular level.

Topics: alpha-Synuclein; Brain; Cell Differentiation; Disease Progression; Humans; Parkinson Disease

Alpha-synuclein (α-syn) has been suggested to have many functions including, vesicle transport in neurons, transcriptional regulator, modulator of immune cell maturation and response, and a role as an antimicrobial peptide. This protein forms insoluble aggregates, called Lewy bodies, in several neurodegenerative diseases, termed synucleinopathies, including Parkinson's disease (PD), Multiple System Atrophy, and Lewy Body Dementia, and aggregates are also commonly found in Alzheimer's disease. Moreover, multiplications and point mutations in the gene cause rare autosomal dominant forms of parkinsonism, which resemble sporadic PD. It has been suggested that the accumulation of α-syn in the monomeric state followed by aggregation of the protein and seeding of further pathogenic α-syn aggregates are key steps in the pathogenesis of synucleinopathies. The triggers of α-syn aggregation in neurodegeneration are unknown, but inflammation caused by bacterial and viral pathogens or exposure to environmental toxins have been implicated. The purpose of this review is to present emerging evidence that α-syn may play a role in the immune response to pathogens. We present recent findings suggesting that upregulation of α-syn levels is a normal response to infections. We propose that under certain conditions (e.g., dysregulated inflammatory responses due to genetic predisposition and aging), monomeric α-syn will form oligomers that are taken up by nerve endings and undergo axonal transport to the central nervous system, where they can aggregate into pathogenic fibrils. Under unfavorable conditions, we suggest that this process can trigger neurodegenerative disease. Therefore, a deeper understanding of the roles of α-syn in the immune system could provide crucial insights into the origins of synucleinopathies.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Multiple System Atrophy; Parkinson Disease; Up-Regulation

Parkinson's disease (PD) is the second-most common neurodegenerative disease in the world, affecting up to 10 million people. This disease mainly happens due to the loss of dopaminergic neurons accountable for memory and motor function. Partial glucocerebrosidase enzyme deficiency and the resultant excess accumulation of glycosphingolipids and alpha-synuclein (α-syn) aggregation have been linked to predominant risk factors that lead to neurodegeneration and memory and motor defects in PD, with known and unknown causes. An increasing body of evidence uncovers the role of several other lipids and their association with α-syn aggregation, which activates the innate and adaptive immune system and sparks brain inflammation in PD. Here, we review the emerging role of a number of lipids, i.e., triglyceride (TG), diglycerides (DG), glycerophosphoethanolamines (GPE), polyunsaturated fatty acids (PUFA), sphingolipids, gangliosides, glycerophospholipids (GPL), and cholesterols, and their connection with α-syn aggregation as well as the induction of innate and adaptive immune reactions that trigger neuroinflammation in PD.

Topics: Adaptive Immunity; alpha-Synuclein; Animals; Humans; Immunity, Innate; Lipid Metabolism; Neuroinflammatory Diseases; Parkinson Disease; Protein Aggregates

α-Synuclein (αSyn) plays a major role in the pathogenesis of Parkinson's disease (PD), which is the second most common neurodegenerative disease after Alzheimer's disease. The accumulation of αSyn is a pathological hallmark of PD, and mutations in the

Topics: alpha-Synuclein; Animals; Animals, Genetically Modified; Disease Models, Animal; Drosophila melanogaster; Humans; Mutation; Parkinson Disease

Parkinson's disease (PD) is a threatening neurodegenerative disorder that seriously affects patients' life quality. Substantial evidence links the overexpression and abnormal aggregation of alpha-synuclein (α-Syn) to PD. α-Syn has been identified as a characteristic biomarker of PD, which indicates its great value of diagnosis and designing effective therapeutic strategy. This article systematically summarizes the pathogenic process of α-Syn based on recent researches, outlines and compares commonly used analysis and detection technologies of α-Syn. Specifically, the detection of α-Syn by new electrochemical, photochemical, and crystal biosensors is mainly examined. Furthermore, the speculation of future study orientation is discussed, which provides reference for the further research and application of α-Syn as biomarker.

Topics: alpha-Synuclein; Biomarkers; Biosensing Techniques; Humans; Parkinson Disease

Dysfunction of the endolysosomal system is implicated in the pathogenesis of both sporadic and familial Parkinson disease (PD). Variants in genes encoding lysosomal proteins have been estimated to be associated with more than half of PD cases. The most common genetic risk factor for PD are variants in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. In this review we will describe the clinical symptoms and pathology of GBA-PD, and how this might be affected by the type of GBA variant. The putative mechanisms by which GCase deficiency in neurons and glia might contribute to PD pathogenesis will then be discussed, with particular emphasis on the accumulation of α-synuclein aggregates and the spread of pathogenic α-synuclein species between the cell types. The dysregulation of not only sphingolipids, but also phospholipids and cholesterol in the misfolding of α-synuclein is reviewed, as are neuroinflammation and the interaction of GCase with LRRK2 protein, another important contributor to PD pathogenesis. Study of both non-manifesting GBA carriers and GBA-PD cohorts provides an opportunity to identify robust biomarkers for PD progression as well as clinical trials for potential treatments. The final part of this review will describe preclinical studies and clinical trials for increasing GCase activity or reducing toxic substrate accumulation.

Topics: alpha-Synuclein; Glucosylceramidase; Heterozygote; Humans; Lysosomes; Mutation; Parkinson Disease

Progress in developing disease-modifying therapies in Parkinson's disease (PD) can only be achieved through reliable objective markers that help to identify subjects at risk. This includes an early and accurate diagnosis as well as continuous monitoring of disease progression and therapy response. Although PD diagnosis still relies mainly on clinical features, encouragingly, advances in biomarker discovery have been made. The cerebrospinal fluid (CSF) is a biofluid of particular interest to study biomarkers since it is closest to the brain structures and therefore could serve as an ideal source to reflect ongoing pathologic processes. According to the key pathophysiological mechanisms, the CSF status of α-synuclein species, markers of amyloid and tau pathology, neurofilament light chain, lysosomal enzymes and markers of neuroinflammation provide promising preliminary results as candidate biomarkers. Untargeted approaches in the field of metabolomics provide insights into novel and interconnected biological pathways. Markers based on genetic forms of PD can contribute to identifying subgroups suitable for gene-targeted treatment strategies that might also be transferable to sporadic PD. Further validation analyses in large PD cohort studies will identify the CSF biomarker or biomarker combinations with the best value for clinical and research purposes.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Biomarkers; Disease Progression; Humans; Parkinson Disease; Peptide Fragments; tau Proteins

A major hallmark of Parkinson's disease (PD) is the fatal destruction of dopaminergic neurons within the

Topics: alpha-Synuclein; Animals; Autophagy; Ferritins; Humans; Iron; Parkinson Disease

Patients with Parkinson's disease (PD) and other synucleinopathies often exhibit autoimmune features, including CD4+ and some CD8+ T lymphocytes that recognize epitopes derived from alpha-synuclein. While neurons have long been considered to not present antigens, recent data indicate that they can be induced to do so, particularly in response to interferons and other forms of stress. Here, we review literature on neuronal antigen presentation and its potential role in PD. Although direct evidence for CD8+ T cell-mediated neuronal death is lacking in PD, neuronal antigen presentation appears central to the pathology of Rasmussen's encephalitis, a pediatric neurological disorder driven by cytotoxic T cell infiltration and neuroinflammation. Emerging data suggest that T cells enter the brain in PD and other synucleinopathies, where the majority of neuromelanin-containing substantia nigra and locus coeruleus neurons express MHC Class I molecules. In cell culture, CD8+ T cell recognition of antigen:MHC Class I complexes on neuronal membranes leads to cytotoxic responses and neuronal cell death. Recent animal models suggest the possibility of T cell autoreactivity to mitochondrial antigens in PD. It remains unclear if neuronal antigen presentation plays a role in PD or other neurodegenerative disorders, and efforts are underway to better elucidate the potential impact of autoimmune responses on neurodegeneration.

Topics: alpha-Synuclein; Animals; Epitopes; Histocompatibility Antigens Class I; Interferons; Neurons; Parkinson Disease; Synucleinopathies

Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron loss and the formation of cytoplasmic protein inclusions. Although the exact pathogenesis of PD is unknown, iron dyshomeostasis has been proposed as a potential contributing factor. Emerging evidence suggests that glial cell activation plays a pivotal role in ferroptosis and subsequent neurodegeneration. We review the association between iron deposition, glial activation, and neuronal death, and discuss whether and how ferroptosis affects α-synuclein aggregation and DA neuron loss. We examine the possible roles of different types of glia in mediating ferroptosis in neurons. Lastly, we review current PD clinical trials targeting iron homeostasis. Although clinical trials are already evaluating ferroptosis modulation in PD, much remains unknown about metal ion metabolism and regulation in PD pathogenesis.

Topics: alpha-Synuclein; Cell Death; Dopaminergic Neurons; Ferroptosis; Humans; Neuroglia; Parkinson Disease

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and motor dysfunction has been attributed to loss of dopaminergic neurons. However, motor dysfunction is only one of many symptoms experienced by patients. A neuropathological hallmark of PD is intraneuronal protein aggregates called Lewy pathology (LP). Neuropathological staging studies have shown that dopaminergic neurons are only one of the many cell types prone to manifest LP. Progressive appearance of LP in multiple brain regions, as well as peripheral nerves, has led to the popular hypothesis that LP and misfolded forms of one of its major components - α-synuclein (aSYN) - can spread through synaptically connected circuits. However, not all brain regions or neurons within connected circuits develop LP, suggesting that cell autonomous factors modulate the development of pathology. Here, we review studies about how LP develops and progressively engages additional brain regions. We focus on how connectivity constrains progression and discuss cell autonomous factors that drive pathology development. We propose a mixed model of cell autonomous factors and trans-synaptic spread as mediators of pathology progression and put forward this model as a framework for future experiments exploring PD pathophysiology.

Topics: alpha-Synuclein; Dopaminergic Neurons; Humans; Parkinson Disease; Phenotype; Synucleinopathies

α-Synucleinopathies including idiopathic Parkinson's disease, dementia with Lewy bodies and multiple systems atrophy share overlapping symptoms and pathological hallmarks. Selective neurodegeneration and Lewy pathology are the main hallmarks of α-synucleinopathies. Currently, there is no imaging biomarker suitable for a definitive early diagnosis of α-synucleinopathies. Although dopaminergic deficits detected with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) radiotracers can support clinical diagnosis by confirming the presence of dopaminergic neurodegeneration, dopaminergic imaging cannot visualize the preceding disease process, nor distinguish α-synucleinopathies from tauopathies with dopaminergic neurodegeneration, especially at early symptomatic disease stage when clinical presentation is often overlapping. Aggregated α-synuclein (αSyn) could be a suitable imaging biomarker in α-synucleinopathies, because αSyn aggregation and therefore, Lewy pathology is evidently an early driver of α-synucleinopathies pathogenesis. Additionally, several antibodies and small molecule compounds targeting aggregated αSyn are in development for therapy. However, there is no way to directly measure if or how much they lower the levels of aggregated αSyn in the brain. There is clearly a paramount diagnostic and therapeutic unmet medical need. To date, aggregated αSyn and Lewy pathology inclusion bodies cannot be assessed ante-mortem with SPECT or PET imaging because of the suboptimal binding characteristics and/or physicochemical properties of current radiotracers. The aim of this narrative review is to highlight the suitability of aggregated αSyn as an imaging biomarker in α-synucleinopathies, the current limitations with and lessons learned from αSyn radiotracer development, and finally to propose antibody-based ligands for imaging αSyn aggregates as a complementary tool rather than an alternative to small molecule ligands. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Topics: alpha-Synuclein; Biomarkers; Humans; Lewy Bodies; Ligands; Parkinson Disease; Synucleinopathies

Parkinson's disease (PD) is a neurodegenerative disorder characterized classically by motor manifestations. However, nonmotor symptoms appear early in the course of the disease progression, making both diagnosis and treatment difficult. The pathology of PD is complicated by the accumulation and aggregation of misfolded proteins in intracellular cytoplasmic inclusions called Lewy bodies (LBs). The main toxic component of LBs is the protein α-Synuclein which plays a pivotal role in PD pathogenesis. α-Synuclein can propagate from cell-to-cell exhibiting prion-like properties and spread PD pathology throughout the central nervous system. Immunotherapeutic interventions in PD, both active and passive immunization, have targeted α-Synuclein in both experimental models and clinical trials. In addition, targeting the hyperactive inflammation in PD also holds promise in designing potential immunotherapeutics. The inflammatory and proteotoxic pathways are interlinked and contribute immensely to the disease pathology. In this chapter, we critically review the targets of immunotherapeutic interventions in PD, focusing on the pathogenetic mechanisms of PD, particularly neuroinflammation and α-Synuclein misfolding, aggregation, and propagation. We thoroughly summarized the various immunotherapeutic strategies designed to treat PD-in vitro, in vivo, and clinical trials. The development of these targeted immunotherapies could open a new avenue in the treatment of patients with PD.

Topics: alpha-Synuclein; Humans; Immunotherapy; Lewy Bodies; Parkinson Disease

Immune changes occur in all neurodegenerative conditions, but there are significant differences between diseases. For Parkinson's disease (PD), the immune system involvement is still being identified with considerable promise for therapeutic targeting. Post-mortem analyses of PD patient brains and pre-clinical cell and rodent models of PD identify increased inflammation in the brain and an elevation in central and peripheral pro-inflammatory cytokines. The cells involved include activated microglia surrounding degenerating neurons, currently thought to be neuroprotective in early disease stages but detrimental at later stages. Very different astrocytic reactions are found in the PD brain compared to other neurodegenerative conditions, with a loss of normal astrocyte functions contributing to a neurotoxic or dysfunctional phenotype (rather than classical astrogliosis found in all other neurodegenerative conditions). Astrocytes in PD are also actively involved in clearing α-synuclein away from vulnerable neurons, but the eventual accumulation of α-synuclein in their cytoplasm promotes a pro-inflammatory response and contributes to their dysfunctional phenotype and the spreading of PD pathology. Infiltration of peripheral immune cells also occurs in the PD brain, particularly T cells and monocytes. Both CD4 and CD8 T cells occur in regions of cell loss, with cytotoxic CD8 T cells occurring in the earliest stages and CD4 T helper cells occurring with disease progression. Current evidence points towards infiltrating monocytes as also playing a role in neuron death. Further characterisation of the successive molecular changes in both the resident and peripheral immune cells invading the PD brain will provide targets for disease modification.

Topics: alpha-Synuclein; Brain; Humans; Immunity; Microglia; Neurodegenerative Diseases; Parkinson Disease

Several bacterial species can generate hydrogen sulfide (H

Topics: alpha-Synuclein; Bacteria; Humans; Hydrogen Sulfide; Iron; Parkinson Disease

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging clinical manifestations, both neurodegenerative diseases share several facets of their complex pathophysiology. Apart from α-synuclein aggregation, an impairment of mitochondrial functions, defective protein clearance systems and excessive inflammatory responses are consistently observed in the brains of PD as well as DLB patients. Leukotrienes are lipid mediators of inflammatory signaling traditionally known for their role in asthma. However, recent research advances highlight a possible contribution of leukotrienes, along with their rate-limiting synthesis enzyme 5-lipoxygenase, in the pathogenesis of central nervous system disorders. This review provides an overview of in vitro as well as in vivo studies, in summary suggesting that dysregulated leukotriene signaling is involved in the pathological processes underlying PD and DLB. In addition, we discuss how the leukotriene signaling pathway could serve as a future drug target for the therapy of PD and DLB.

Topics: alpha-Synuclein; Brain; Humans; Leukotrienes; Lewy Body Disease; Parkinson Disease; Signal Transduction; Synucleinopathies

Amyloid formation is a pathological process associated with a wide range of degenerative disorders, including Alzheimer's disease, Parkinson's disease, and diabetes mellitus type 2. During disease progression, abnormal accumulation and deposition of proteinaceous material are accompanied by tissue degradation, inflammation, and dysfunction. Agents that can interfere with the process of amyloid formation or target already formed amyloid assemblies are consequently of therapeutic interest. In this context, a few endogenous proteins have been associated with an anti-amyloidogenic activity. Here, we review the properties of transthyretin, apolipoprotein E, clusterin, and BRICHOS protein domain which all effectively interfere with amyloid in vitro, as well as displaying a clinical impact in humans or animal models. Their involvement in the amyloid formation process is discussed, which may aid and inspire new strategies for therapeutic interventions.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloidogenic Proteins; Amyloidosis; Animals; Humans; Parkinson Disease

Topics: alpha-Synuclein; Animals; Disease Progression; Humans; Mammals; Neurodegenerative Diseases; Parkinson Disease; Ubiquitin-Protein Ligases

α-Synuclein aggregation is a critical molecular process that underpins the pathogenesis of Parkinson's disease. Aggregates may originate at synaptic terminals as a consequence of aberrant interactions between α-synuclein and lipids or evasion of proteostatic defences. The nature of these interactions is likely to influence the emergence of conformers or strains that in turn could explain the clinical heterogeneity of Parkinson's disease and related α-synucleinopathies. For neurodegeneration to occur, α-synuclein assemblies need to exhibit seeding competency, i.e. ability to template further aggregation, and toxicity which is at least partly mediated by interference with synaptic vesicle or organelle homeostasis. Given the dynamic and reversible conformational plasticity of α-synuclein, it is possible that seeding competency and cellular toxicity are mediated by assemblies of different structure or size along this continuum. It is currently unknown which α-synuclein assemblies are the most relevant to the human condition but recent advances in the cryo-electron microscopic characterisation of brain-derived fibrils and their assessment in stem cell derived and animal models are likely to facilitate the development of precision therapies or biomarkers. This review summarises the main principles of α-synuclein aggregate initiation and propagation in model systems, and their relevance to clinical translation.

Topics: alpha-Synuclein; Animals; Brain; Parkinson Disease; Synucleinopathies

Parkinson's disease (PD) is a chronic neurodegenerative disease mainly characterized by movement disorders and other non-motor symptoms, including the loss of dopaminergic neurons in the substantia nigra parts. Abnormal α-synuclein aggregation in the brain is closely associated with the loss of dopaminergic neurons. α-synuclein can propagate in the central nervous system (CNS) and periphery under pathological conditions. Many researches have focused on its aggregation and distribution in the CNS and explored its relationship with PD. But in recent years, the distribution of α-synuclein in peripheral tissues have been paid much attention. This review summarized the distribution of α-synuclein in the choroid plexus, blood, saliva, gastrointestine and other tissues, and discussed the potential mechanism of α-synuclein aggregation, providing a basis for the early diagnosis and intervention of PD.

Topics: alpha-Synuclein; Dopaminergic Neurons; Humans; Neurodegenerative Diseases; Parkinson Disease; Substantia Nigra

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive movement disability accompanied by non-motor symptoms. The neuropathology hallmark of PD is the loss of dopaminergic neurons predominantly in the substantia nigra pars compacta and the presence of intracellular inclusions termed Lewy bodies (LBs), which are mainly composed of α-synuclein (αSyn). Detailed staging based on the distribution and progression pattern of αSyn pathology in the postmortem brains of PD patients revealed correlation with the clinical phenotypes but not invariably. Cumulative evidence from cell and animal studies has implied that αSyn propagation contributes to the anatomical spread of αSyn pathology in the brain. Here, we recount the studies over the past two centuries on the anatomopathological foundations of PD documented. We also review studies on the structural analysis of αSyn and LBs, Braak staging of αSyn pathology, the cell-to-cell propagation of αSyn as well as αSyn fibril polymorphisms, which underlie the phenotypic differences in synucleinopathies.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Humans; Lewy Bodies; Neuropathology; Parkinson Disease

A growing amount of evidence has indicated contributions of variants in causative genes of Parkinson's disease (PD) to the development of sleep disturbance in PD and prodromal PD stages. In this article, we aimed to investigate the role of genetics in sleep disorders in PD patients and asymptomatic carriers at prodromal stage of PD. A systematic review and meta-analysis of observational studies was conducted based on the MEDLINE, EMBASE and PsychINFO databases. A pooled effect size was calculated by odds ratio (OR) and standard mean difference (SMD). Forty studies were selected for quantitative analysis, including 17 studies on glucocerebrosidase (GBA), 25 studies on Leucine-rich repeat kinase 2 (LRRK2) and 7 on parkin (PRKN) genes, and 3 studies on alpha-synuclein gene (SNCA) were used for qualitative analysis. Patients with PD carrying GBA variants had a significantly higher risk for rapid-eye-movement behavior disorders (RBD) (OR, 1.82) and higher RBD Screening Questionnaire scores (SMD, 0.33). Asymptomatic carriers of GBA variants had higher severity of RBD during follow-up. Patients with PD carrying the LRRK2 G2019S variant had lower risk and severity of RBD compared with those without LRRK2 G2019S. Variants of GBA, LRRK2 and PRKN did not increase or decrease the risk and severity of excessive daytime sleepiness and restless legs syndrome in PD. Our findings suggest that the genetic heterogeneity plays a role in the development of sleep disorders, mainly RBD, in PD and the prodromal stage of PD.

Topics: alpha-Synuclein; Genetic Heterogeneity; Glucosylceramidase; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease; Prodromal Symptoms; Sleep Wake Disorders

Parkinson's disease (PD) is a common neurodegenerative disease characterized by loss of dopaminergic neurons in the

Topics: alpha-Synuclein; Dopaminergic Neurons; Humans; Immunity; Neurodegenerative Diseases; Parkinson Disease; Substantia Nigra

The clinical presentation of Parkinson's disease (PD) is both complex and heterogeneous, and its precise classification often requires an intensive work-up. The differential diagnosis, assessment of disease progression, evaluation of therapeutic responses, or identification of PD subtypes frequently remains uncertain from a clinical point of view. Various tissue- and fluid-based biomarkers are currently being investigated to improve the description of PD. From a clinician's perspective, signatures from blood that are relatively easy to obtain would have great potential for use in clinical practice if they fulfill the necessary requirements as PD biomarker. In this review article, we summarize the knowledge on blood-based PD biomarkers and present both a researcher's and a clinician's perspective on recent developments and potential future applications.

Topics: alpha-Synuclein; Biomarkers; Diagnosis, Differential; Disease Progression; Humans; Parkinson Disease

Aggregation of specific proteins are histopathological hallmarks of several neurodegenerative diseases, such as, Amyloid β (Aβ) plaques and tau neurofibrillary tangles in Alzheimer's disease (AD); morphologically different inclusions of ratiometric 3 repeat (3 R) and 4 repeat (4 R) tau isoforms in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD); α-Synuclein (α-Syn) containing Lewy bodies (LBs) and dystrophic Lewy neurites (LNs) in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, mixed brain protein pathologies have been frequently observed in many of these diseases and in normal aging brains, among which Aβ/tau and tau/α-Syn crosstalks have received increased attention. Interestingly, studies have also shown synergistic interplay among Aβ, tau, and α-Syn in several neurodegenerative diseases, suggesting a protein triumvirate. In this review, we summarize the emerging evidence of Aβ, tau, and α-Syn aggregation in pathophysiology, and their overlap in a spectrum of neurodegenerative diseases including AD, PSP, PiD, CBD, PD and DLB. We discuss the prognostic advancements made in biomarker and imaging techniques in the triumvirate proteinopathies. Finally, we discuss the combined therapeutic modality involving biomarkers and imaging techniques for future combinatorial immunotherapeutic targeting more than one protein aggregates. We hope that such a multitarget therapeutic approach will have synergistic or additive effects to manage neurodegenerative diseases with two or more protein pathologies that might uncover a promising strategy for personalized combination therapies. Managing neurodegenerative diseases by optimizing the diagnostic criteria and the correct combination of immunotherapies will be a key factor in the success of future treatment.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Humans; Lewy Bodies; Neurodegenerative Diseases; Parkinson Disease; Plaque, Amyloid; Protein Aggregation, Pathological; tau Proteins

α-synuclein (α-syn) is a presynaptic, lipid-binding protein strongly associated with the neuropathology observed in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and Alzheimer's Disease (AD). In normal physiology, α-syn plays a pivotal role in facilitating endocytosis and exocytosis. Interestingly, mutations and modifications of precise α-syn domains interfere with α-syn oligomerization and nucleation that negatively affect presynaptic vesicular dynamics, protein expressions, and mitochondrial profiles. Furthermore, the integration of the α-syn oligomers into the presynaptic membrane results in pore formations, ion influx, and excitotoxicity. Targeted therapies against specific domains of α-syn, including the use of small organic molecules, monoclonal antibodies, and synthetic peptides, are being screened and developed. However, the prospect of an effective α-syn targeted therapy is still plagued by low permeability across the blood-brain barrier (BBB), and poor entry into the presynaptic axon terminals. The present review proposes a modification of current strategies, which includes the use of novel encapsulation technology, such as lipid nanoparticles, to bypass the BBB and deliver such agents into the brain.

Topics: alpha-Synuclein; Humans; Liposomes; Nanoparticles; Parkinson Disease; Presynaptic Terminals

The

Topics: alpha-Synuclein; Endoplasmic Reticulum; Glucosylceramidase; Humans; Lysosomes; Mutation; Parkinson Disease

Multiple system atrophy is a rapidly progressive and fatal neurodegenerative disorder. While numerous preclinical studies suggested efficacy of potentially disease modifying agents, none of those were proven to be effective in large-scale clinical trials. Three major strategies are currently pursued in preclinical and clinical studies attempting to slow down disease progression. These target α-synuclein, neuroinflammation, and restoration of neurotrophic support. This review provides a comprehensive overview on ongoing preclinical and clinical developments of disease modifying therapies. Furthermore, we will focus on potential shortcomings of previous studies that can be avoided to improve data quality in future studies of this rare disease.

Topics: alpha-Synuclein; Humans; Multiple System Atrophy; Parkinson Disease

Over the last decade, researchers have discovered that  a group of apparently unrelated neurodegenerative disorders, such as Parkinson's disease, have remarkable cellular and molecular biology similarities. Protein misfolding and aggregation are involved in all of the neurodegenerative conditions; as a result, inclusion bodies aggregation starts in the cells. Chaperone proteins and ubiquitin (26S proteasome's proteolysis signal), which aid in refolding misfolded proteins, are frequently found in these aggregates. The discovery of disease-causing gene alterations that code for multiple ubiquitin-proteasome pathway proteins in Parkinson's disease has strengthened the relationship between the ubiquitin-proteasome system and neurodegeneration. The specific molecular linkages between these systems and pathogenesis, on the other hand, are unknown and controversial. We outline the current level of knowledge in this article, focusing on important unanswered problems.

Topics: alpha-Synuclein; Humans; Molecular Chaperones; Neurodegenerative Diseases; Parkinson Disease; Proteasome Endopeptidase Complex; Ubiquitin

Immune-related alterations in Parkinson's disease (PD) can be monitored by assessing peripheral biological fluids that show that specific inflammatory pathways contribute to a chronic pro-inflammatory status. This pro-inflammatory activity is hypothesized to be already present in the prodromal stages of PD. These pathways maintain and reinforce chronic neurodegeneration by stimulating cell activation and proliferation what triggers the pro-inflammatory status as well. The gut microbiome possibly contributes to inflammatory pathways and shows specific differences in fecal samples from PD compared to healthy controls. In PD, Bacteroides abundance correlates with inflammatory markers in blood and motor impairment. Increased pro-inflammatory and decreased anti-inflammatory bacterial colonization can lead to changes in the metabolic pathways of amino acids, inducing increased membrane permeability, described as a leaky gut, enabling advanced contact between immune cells and gut microbiome and potentially a spreading of neuroinflammation through the body via the blood. Increased cytokine blood levels in PD are correlated with disease severity, motor symptoms, and clinical phenotypes. α-synuclein is a central player in PD-associated inflammation, inducing specific T-cell activity and triggering microglial activation in the central nervous system (CNS). Misfolded α-synuclein propagation possibly results in the spreading of aggregated α-synuclein from neuron to neuron leading to a sustained neuroinflammation. This is supported by age-dependent defects of protein uptake in microglia and monocytes, so-called "inflammaging", including α-synuclein oligomers, as the key pathological protein in PD. Genetic risk markers and inherited forms of PD are also associated with inflammation, which is highly relevant for potential therapeutical targets. The documented associations of inflammatory markers and clinical phenotypes indicate a pro-inflammatory concept of specific PD pathophysiology here. An in-depth understanding of inflammatory mechanisms in PD from bottom (gut) to top (CNS) and vice versa is needed to design novel immunomodulatory approaches to delay or even stop PD. Future studies focusing on structured protocols in large patient cohorts with appropriate control groups and comparative analysis among studies will aid the discovery of novel candidate biomarkers.

Topics: alpha-Synuclein; Biomarkers; Humans; Inflammation; Microglia; Monocytes; Parkinson Disease

The degeneration of nigral dopaminergic neurons is considered the hallmark of Parkinson's disease (PD), and it is triggered by different factors, including mitochondrial dysfunction, Lewy body accumulation, neuroinflammation, excitotoxicity and metal accumulation. Despite the extensive literature devoted to unravelling the signalling pathways involved in neuronal degeneration, little is known about the functional impairments occurring in these cells during illness progression. Of course, it is not possible to obtain direct information on the properties of the dopaminergic cells in patients. However, several data are available in the literature reporting changes in the function of these cells in PD animal models. In the present manuscript, we focus on dopaminergic neuron functional properties and summarize shared or peculiar features of neuronal dysfunction in different PD animal models at different stages of the disease in an attempt to design a picture of the functional modifications occurring in nigral dopaminergic neurons during disease progression preceding their eventual death.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Dopaminergic Neurons; Humans; Parkinson Disease; Substantia Nigra

Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by the loss of dopaminergic neurons in the substantia nigra and the abnormal aggregation and accumulation of the alpha-synuclein (α-syn) protein into Lewy bodies. It is established that there is an association between inflammation and PD; however, the time course of the inflammatory process as well as the immune cells involved are still debated. Natural killer (NK) cells are innate lymphocytes with numerous functions including targeting and killing infected or malignant cells, antimicrobial defense, and resolving inflammation. NK cell subsets differ in their effector function capacities which are modulated by activating and inhibitory receptors expressed at the cell surface. Alterations in NK cell numbers and receptor expression have been reported in PD patients. Recently, NK cell numbers and frequency were shown to be altered in the periphery and in the central nervous system in a preclinical mouse model of PD. Moreover, NK cells have recently been shown to internalize and degrade α-syn aggregates and systemic NK cell depletion exacerbated synuclein pathology in a preclinical mouse model of PD, indicating a potential protective role of NK cells. Here, we review the inflammatory process in PD with a particular focus on alterations in NK cell numbers, phenotypes, and functions.

Topics: alpha-Synuclein; Animals; Inflammation; Killer Cells, Natural; Mice; Neurodegenerative Diseases; Parkinson Disease

Advanced research in health science has broadened our view in approaching and understanding the pathophysiology of diseases and has also revolutionised diagnosis and treatment. Ever since the establishment of Braak's hypothesis in the propagation of alpha-synuclein from the distant olfactory and enteric nervous system towards the brain in Parkinson's Disease (PD), studies have explored and revealed the involvement of altered gut microbiota in PD. This review recapitulates the gut microbiome associated with PD severity, duration, motor and non-motor symptoms, and antiparkinsonian treatment from recent literature. Gut microbial signatures in PD are potential predictors of the disease and are speculated to be used in early diagnosis and treatment. In brief, the review also emphasises on implications of the prebiotic, probiotic, faecal microbiota transplantation, and dietary interventions as alternative treatments in modulating the disease symptoms in PD.

Topics: alpha-Synuclein; Antiparkinson Agents; Brain; Gastrointestinal Microbiome; Humans; Parkinson Disease

Parkinson's disease (PD) is a common central nervous system disorder (CNS) characterized by cell loss in the substantia nigra. Severe loss of dopaminergic neurons and Lewy body formation with α-synuclein inclusions are the main neuropathological features of PD. There's currently no cure for PD, but treatments are available to help relieve the symptoms and maintain quality of life. However, the variety of clinically available therapeutic molecules is mainly limited to treating symptoms rather than halting or reversing disease progression via medical interventions. As an emerging drug carrier, hydrogels loaded with therapeutic agents and cells are attracting attention as an alternative and potentially more effective approach to managing PD. The current work highlights applications of hydrogel-based biomaterials in cell culture and disease modeling as carriers for cells, medicines, and proteins as PD therapeutic models.

Topics: alpha-Synuclein; Drug Delivery Systems; Humans; Hydrogels; Parkinson Disease; Quality of Life; Substantia Nigra

α-synuclein (α-syn) is a highly conserved and thermostable protein that is widely distributed in human brain. An intracellular aggregation of α-syn in dopaminergic neurons is the hallmark of a group of neurodegenerative diseases including Parkinson's disease. Interestingly, α-syn is also highly expressed in red blood cells and is considered as one of the most abundant proteins in red blood cells. Moreover, α-syn is thought to play a regulatory role during normal erythropoiesis. However, whether α-syn participates in the pathogenesis of erythroid diseases has not been reported. In this review, we discuss the protein structure of α-syn and the importance of α-syn in erythropoiesis.

Topics: alpha-Synuclein; Brain; Erythropoiesis; Humans; Neurodegenerative Diseases; Parkinson Disease

Lewy body dementia encompasses the common neurodegenerative disorders Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Lewy Body disease (LBD) is characterized by abnormal aggregates of α-synuclein (α-syn) in the brain which form Lewy bodies. LBD is commonly misdiagnosed/underdiagnosed, especially in early stages. There remains a great need for reliable biomarkers to assist with LBD diagnosis. Amplification techniques such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) represent an important advance for biomarker detection. Amplification assays detect the ability of pathogenic protein to induce conformational change in normal protein; α-syn has been shown to propagate in a prion-like manner, making it a candidate for such analysis. In this review, we describe the diagnostic potential of amplification techniques for differentiating α-synucleinopathies from other neurodegenerative disorders such as Alzheimer's disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and atypical parkinsonism, as well as α-synucleinopathies from each other. Recent studies report accurate detection of α-syn seeding activity in human tissues such as cerebrospinal fluid (CSF), submandibular gland (SMG), and posterior cervical skin. Adaptation to clinical settings may present challenges. However, the high accuracy of recent results, combined with the success of amplification assay diagnostics in clinical practice for Creutzfeldt-Jakob disease, suggest high promise for eventual clinical application.

Topics: alpha-Synuclein; Alzheimer Disease; Biomarkers; Dementia; Humans; Lewy Body Disease; Parkinson Disease; Synucleinopathies

Alpha-synuclein (α-syn) is a small protein composed of 140 amino acids and belongs to the group of intrinsically disordered proteins. It is a soluble protein that is highly expressed in neurons and expressed at low levels in glial cells. The monomeric protein aggregation process induces the formation of oligomeric intermediates and proceeds towards fibrillar species. These α-syn conformational species have been detected in the extracellular space and mediate consequences on surrounding neurons and glial cells. In particular, higher-ordered α-syn aggregates are involved in microglial and oligodendrocyte activation, as well as in the induction of astrogliosis. These phenomena lead to mitochondrial dysfunction, reactive oxygen and nitrogen species formation, and the induction of an inflammatory response, associated with neuronal cell death. Several receptors participate in cell activation and/or in the uptake of α-syn, which can vary depending on the α-syn aggregated state and cell types. The receptors involved in this process are of outstanding relevance because they may constitute potential therapeutic targets for the treatment of PD and related synucleinopathies. This review article focuses on the mechanism associated with extracellular α-syn uptake in glial cells and the consequent glial cell activation that contributes to the neuronal death associated with synucleinopathies.

Topics: alpha-Synuclein; Humans; Neuroglia; Parkinson Disease; Protein Aggregates; Synucleinopathies

Parkinson's disease (PD), as a debilitating neurodegenerative disease, particularly affects the elderly population, and is clinically identified by resting tremor, rigidity, and bradykinesia. Pathophysiologically, PD is characterized by an early loss of dopaminergic neurons in the Substantia nigra pars compacta, accompanied by the extensive aggregation of alpha-synuclein (α-Syn) in the form of Lewy bodies. The onset of PD has been reported to be influenced by multiple biological molecules. In this context, circular RNAs (circRNAs), as tissue-specific noncoding RNAs with closed structures, have been recently demonstrated to involve in a set of PD's pathogenic processes. These RNA molecules can either up- or downregulate the expression of α-Syn, as well as moderating its accumulation through different regulatory mechanisms, in which targeting microRNAs (miRNAs) is considered the most common pathway. Since circRNAs have prominent structural and biological characteristics, they could also be considered as promising candidates for PD diagnosis and treatment. Unfortunately, PD has become a global health concern, and a large number of its pathogenic processes are still unclear; thus, it is crucial to elucidate the ambiguous aspects of PD pathophysiology to improve the efficiency of diagnostic and therapeutic strategies. In line with this fact, the current review aims to highlight the interplay between circRNAs and PD pathogenesis, and then discusses the diagnostic and therapeutic potential of circRNAs in PD progression. This study will thus be the first of its kind reviewing the relationship between circRNAs and PD.

Topics: Aged; alpha-Synuclein; Dopaminergic Neurons; Humans; MicroRNAs; Neurodegenerative Diseases; Parkinson Disease; RNA, Circular

Parkinson's disease (PD) is a neurodegenerative disease characterized pathologically by the formation of Lewy bodies comprised mainly of α-synuclein. Assessment of skin synuclein has the potential as an excellent diagnostic method with high sensitivity, specificity, and reproducibility that is also convenient and acceptable to patients. In this review, we summarize findings regarding the characteristics of cutaneous nerve p-α-syn or α-syn deposits and their correlations with clinical phenotypes in PD patients with and without orthostatic hypotension and LRRK2, GBA, and SNCA gene mutations. This review can serve as a reference for the diagnosis and classification of PD based on α-syn deposit patterns and to deeply explore its pathogenesis. FUNDING STATEMENT: The work was partly supported by the National Natural Science Key Foundation of China (No. 81830040 and No 82130042) and the Program of Excellent Talents in Medical Science of Jiangsu Province (No. JCRCA2016006) .

Topics: alpha-Synuclein; Gene Expression; Humans; Neurodegenerative Diseases; Parkinson Disease; Reproducibility of Results

Intracellular deposition of alpha-synuclein (α-syn) as Lewy bodies and Lewy neurites is a central event in the pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies. Transgenic mouse models overexpressing human α-syn, are useful research tools in preclinical studies of pathogenetic mechanisms. Such mice develop α-syn inclusions as well as neurodegeneration with a topographical distribution that varies depending on the choice of promoter and which form of α-syn that is overexpressed. Moreover, they display motor symptoms and cognitive disturbances that to some extent resemble the human conditions.. One of the main motives for assessing behavior in these mouse models is to evaluate the potential of new treatment strategies, including their impact on motor and cognitive symptoms. However, due to a high within-group variability with respect to such features, the behavioral studies need to be applied with caution. In this review, we discuss how to make appropriate choices in the experimental design and which tests that are most suitable for the evaluation of PD-related symptoms in such studies.. We have evaluated published results on two selected transgenic mouse models overexpressing wild type (L61) and mutated (A30P) α-syn in the context of their validity and utility for different types of behavioral studies.. By applying appropriate behavioral tests, α-syn transgenic mouse models provide an appropriate experimental platform for studies of symptoms related to PD and other α-synucleinopathies.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Humans; Lewy Bodies; Mice; Mice, Transgenic; Parkinson Disease; Synucleinopathies

Accumulating evidence suggests that microglia and peripheral immune cells may play determinant roles in the pathogenesis of Parkinson's disease (PD). Consequently, there is a need to take advantage of immune-related models of PD to study the potential contribution of microglia and peripheral immune cells to the degeneration of the nigrostriatal system and help develop potential therapies for PD. In this review, we have summarised the main PD immune models. From a historical perspective, we highlight first the main features of intranigral injections of different pro-inflammogens, including lipopolysaccharide (LPS), thrombin, neuromelanin, etc. The use of adenoviral vectors to promote microglia-specific overexpression of different molecules in the ventral mesencephalon, including α-synuclein, IL-1β, and TNF, are also presented and briefly discussed. Finally, we summarise different models associated with peripheral inflammation whose contribution to the pathogenesis of neurodegenerative diseases is now an outstanding question. Illustrative examples included systemic LPS administration and dextran sulfate sodium-induced colitis in rodents.

Topics: alpha-Synuclein; Animals; Dextran Sulfate; Disease Models, Animal; Lipopolysaccharides; Microglia; Models, Animal; Parkinson Disease; Substantia Nigra; Thrombin

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder. PD is characterized by progressive loss of dopamine-producing neurons in the substantia nigra (SN) region of brain tissue followed by the α-synuclein-based Lewy bodies' formation. These conditions are manifested by various motor and non-motor symptoms such as resting tremor, limb rigidity, bradykinesia and posture instability, cognitive impairment, sleep disorders, and emotional and memory dysfunctions. Long non-coding RNAs (lncRNAs) are closely related to protein-coding genes and are involved in various biological processes. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) lncRNA is involved in different pathways, including alternative splicing, transcriptional regulation, and post-transcriptional regulation, and also interacts with RNAs as a miRNA sponge. MALAT1 is highly expressed in brain tissues and several lines of evidence suggested it is probably involved in synapse generation and other neurophysiological pathways. This narrative review discussed all aspects of MALAT1-associated mechanisms involved in the PD pathogenesis, i.e., perturbed α-synuclein homeostasis, apoptosis and autophagy, and neuro-inflammation. Lastly, the possible applications of MALAT1 as a diagnostic biomarker and its importance to developing therapeutic strategies were highlighted. The literature search was conducted using neurodegeneration, neurodegenerative disorders, Parkinson's disease, lncRNA, and MALAT1 as search items in Google Scholar, Web of Knowledge, PubMed, and Scopus up to December 2021.

Topics: alpha-Synuclein; Alternative Splicing; Humans; MicroRNAs; Parkinson Disease; RNA, Long Noncoding

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neurodegeneration and deposition of alpha-synuclein. Mechanisms associated with PD etiology include oxidative stress, apoptosis, autophagy, and abnormalities in neurotransmission, to name a few. Drugs used to treat PD have shown significant limitations in their efficacy. Therefore, recent focus has been placed on the potential of active plant ingredients as alternative, complementary, and efficient treatments. Berberine is an isoquinoline alkaloid that has shown promise as a pharmacological treatment in PD, given its ability to modulate several molecular pathway associated with the disease. Here, we review contemporary knowledge supporting the need to further characterize berberine as a potential treatment for PD.

Topics: alpha-Synuclein; Autophagy; Berberine; Dopaminergic Neurons; Humans; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Among its pathologies, progressive loss of dopaminergic (DA) neurons in the substantia nigra is characteristic and contributes to many of the most severe symptoms of PD. Recent advances in induced pluripotent stem cell (iPSC) technology have made it possible to generate patient-derived DA neuronal cell culture and organoid models of PD. These models have contributed to understanding disease mechanisms and the identification of novel targets and therapeutic candidates. Still needed are better ways to model the age-related aspects of PD, as well as a deeper understanding of the interactions among disease-modifying genes and between genetic and environmental contributions to the etiology and progression of PD.

Topics: alpha-Synuclein; Dopaminergic Neurons; Humans; Induced Pluripotent Stem Cells; Parkinson Disease

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, characterized by motor and non-motor symptoms, significantly affecting patients' life. Pathologically, PD is associated with the extensive degeneration of dopaminergic neurons in various regions of the central nervous system (CNS), specifically the substantia nigra. This neuronal loss is accompanied by the aggregation of misfolded protein, named α-synuclein.. Recent studies detected several clues of neuroinflammation in PD samples using postmortem human PD brains and various PD animal models. Some evidence of neuroinflammation in PD patients included higher levels of proinflammatory cytokines in serum and cerebrospinal fluid (CSF), presence of activated microglia in various brain regions such as substantia nigra, infiltration of peripheral inflammatory cells in affected brain regions, and altered function of cellular immunity like monocytes phagocytosis defects. On the other side, Toll-like receptors (TLRs) are innate immune receptors primarily located on microglia, as well as other immune and non-immune cells, expressing pivotal roles in recognizing exogenous and endogenous stimuli and triggering inflammatory responses. Most studies indicated an increased expression of TLRs in the brain and peripheral blood cells of PD samples. Besides, this upregulation was associated with excessive neuroinflammation followed by neurodegeneration in affected regions. Therefore, evidence proposed that TLR-mediated neuroinflammation might lead to a dopaminergic neural loss in PD patients. In this regard, TLR2, TLR4, and TLR9 have the most prominent roles.. Although the presence of inflammation in acute phases of PD might have protective effects concerning the clearance of α-synuclein and delaying the disease advancement, the chronic activation of TLRs and neuroinflammation might lead to neurodegeneration, resulting in the disease progression. Therefore, this study aimed to review additional evidence of the contribution of TLRs and neuroinflammation to PD pathogenesis, with the hope that TLRs could serve as novel disease-modifying therapeutic targets in PD patients in the future.

Topics: alpha-Synuclein; Animals; Humans; Microglia; Neuroinflammatory Diseases; Parkinson Disease; Substantia Nigra; Toll-Like Receptors

Membrane interfaces are vital for various cellular processes, and their involvement in neurodegenerative disorders such as Alzheimer's and Parkinson's disease has taken precedence in recent years. The amyloidogenic proteins associated with neurodegenerative diseases interact with the neuronal membrane through various means, which has implications for both the onset and progression of the disease. The parameters that regulate the interaction between the membrane and the amyloids remain poorly understood. The review focuses on the various aspects of membrane interactions of amyloids, particularly amyloid-β (Aβ) peptides and Tau involved in Alzheimer's and α-synuclein involved in Parkinson's disease. The genetic, cell biological, biochemical, and biophysical studies that form the basis for our current understanding of the membrane interactions of Aβ peptides, Tau, and α-synuclein are discussed.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Humans; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder which affects 6.1 million people worldwide. The neuropathological hallmarks include the loss of dopaminergic neurons in the substantia nigra, the presence of Lewy bodies and Lewy neurites caused by α-synuclein aggregation, and neuroinflammation in the brain. The prodromal phase happens years before the onset of PD during which time many patients show gastro-intestinal symptoms. These symptoms are in support of Braak's theory and model where pathological α-synuclein propagates from the gut to the brain. Importantly, immune responses play a determinant role in the pathogenesis of Parkinson's disease. The innate immune responses triggered by microglia can cause neuronal death and disease progression. In addition, T cells infiltrate into the brains of PD patients and become involved in the adaptive immune responses. Interestingly, α-synuclein is associated with both innate and adaptive immune responses by directly interacting with microglia and T cells. Here, we give a detailed review of the immunobiology of Parkinson's disease, focusing on the role α-synuclein in the gut-brain axis hypothesis, the innate and adaptive immune responses involved in the disease, and current treatments.

Topics: alpha-Synuclein; Brain; Dopaminergic Neurons; Humans; Neurodegenerative Diseases; Parkinson Disease

Following Alzheimer's, Parkinson's disease (PD) is the second-most common neurodegenerative disorder, sharing an unclear pathophysiology, a multifactorial profile, and massive social costs worldwide. Despite this, no disease-modifying therapy is available. PD is tightly associated with α-synuclein (α-Syn) deposits, which become organised into insoluble, amyloid fibrils. As a typical intrinsically disordered protein, α-Syn adopts a monomeric, random coil conformation in an aqueous solution, while its interaction with lipid membranes drives the transition of the molecule part into an α-helical structure. The central unstructured region of α-Syn is involved in fibril formation by converting to well-defined, β-sheet rich secondary structures. Presently, most therapeutic strategies against PD are focused on designing small molecules, peptides, and peptidomimetics that can directly target α-Syn and its aggregation pathway. Other approaches include gene silencing, cell transplantation, stimulation of intracellular clearance with autophagy promoters, and degradation pathways based on immunotherapy of amyloid fibrils. In the present review, we sum marise the current advances related to α-Syn aggregation/neurotoxicity. These findings present a valuable arsenal for the further development of efficient, nontoxic, and non-invasive therapeutic protocols for disease-modifying therapy that tackles disease onset and progression in the future.

Topics: alpha-Synuclein; Amyloid; Humans; Intrinsically Disordered Proteins; Parkinson Disease; Protein Conformation, beta-Strand

α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the

Topics: alpha-Synuclein; Humans; Lewy Bodies; Parkinson Disease; Phosphorylation; Synucleinopathies

Synuclein aggregation in neuronal cells is the primary underlying cause of synucleinopathies. Changes in gene expression patterns, structural modifications, and altered interactions with other cellular proteins often trigger aggregation of α-synuclein, which accumulates as oligomers or fibrils in Lewy bodies. Although fibrillar forms of α-synuclein are primarily considered pathological, recent studies have revealed that even the intermediate states of aggregates are neurotoxic, complicating the development of therapeutic interventions. Autophagy and ubiquitin-proteasome pathways play a significant role in maintaining the soluble levels of α-synuclein inside cells; however, the heterogeneous nature of the aggregates presents a significant bottleneck to its degradation by these cellular pathways. With studies focused on identifying the proteins that modulate synuclein aggregation and clearance, detailed mechanistic insights are emerging about the individual and synergistic effects of these degradation pathways in regulating soluble α-synuclein levels. In this article, we discuss the impact of α-synuclein aggregation on autophagy-lysosome and ubiquitin-proteasome pathways and the therapeutic strategies that target various aspects of synuclein aggregation or degradation via these pathways. Additionally, we also highlight the natural and synthetic compounds that have shown promise in alleviating the cellular damage caused due to synuclein aggregation.

Topics: alpha-Synuclein; Autophagy; Humans; Lysosomes; Parkinson Disease; Proteasome Endopeptidase Complex; Ubiquitin

Reliable biomarkers for Parkinson's disease (PD) diagnosis are urgently needed. Alpha-synuclein (α-syn) and its proteoforms play a key role in PD pathology but in vivo measurements have raised conflicting results, and whether α-syn in blood could distinguish PD patients from healthy controls is still controversial.. A systematic literature search yielded 35 eligible studies for meta-analysis reporting the concentration of total, oligomeric or phosphorylated α-syn in plasma and/or serum of PD patients and healthy controls. Standardized mean differences (SMD) were pooled using multivariate/multilevel linear mixed-effects models. Meta-regression analyses were conducted to investigate possible modifiers.. A meta-analysis of 32 articles involving 2683 PD patients and 1838 controls showed a significant overall effect of PD on total α-syn levels (SMD = 0.85, p = 0.004). Meta-regression showed that increased SMD of total α-syn in PD was significantly associated with lower age, shorter disease duration, mild motor impairment, and Immunomagnetic Reduction assay for protein quantification. In contrast, no significant differences were observed for oligomeric or phosphorylated α-syn between PD and controls but increased oligomeric α-syn was significantly associated with shorter disease duration. The heterogeneity among studies was high (>98%).. These findings suggest that increased total plasma/serum α-syn levels in PD primarily occur in early phases of the disease. The evidence obtained from a small number of studies measuring plasma/serum concentrations of oligomeric and phosphorylated species of α-syn shows no difference. The clinical applicability of measuring plasma or serum α-syn species for differentiating PD from healthy control warrants further studies with better clinical profiling of PD patients.

Topics: alpha-Synuclein; Biomarkers; Humans; Parkinson Disease

Multiple lines of clinical and pre-clinical research support a pathogenic role for neuroinflammation and peripheral immune system dysfunction in Parkinson's disease. In this paper, we have reviewed and summarised the published literature reporting evidence of neuroinflammation and peripheral immune changes in cohorts of patients with isolated REM sleep behaviour disorder and non-manifesting carriers of GBA or LRRK2 gene mutations, who have increased risk for Parkinsonism and synucleinopathies, and could be in the prodromal stage of these conditions. Taken together, the findings of these studies suggest that the early stages of pathology in Parkinsonism involve activation of both the central and peripheral immune systems with significant crosstalk. We consider these findings with respect to those found in patients with clinical Parkinson's disease and discuss their possible pathological roles. Moreover, those factors possibly associated with the immune response, such as the immunomodulatory role of the affected neurotransmitters and the changes in the gut-brain axis, are also considered.

Topics: alpha-Synuclein; Humans; Neuroinflammatory Diseases; Parkinson Disease; Prodromal Symptoms; REM Sleep Behavior Disorder; Synucleinopathies

Together with neuronal loss, the existence of insoluble inclusions of alpha-synuclein (α-syn) in the brain is widely accepted as a hallmark of synucleinopathies including Parkinson's disease (PD), multiple system atrophy, and dementia with Lewy body. Because the α-syn aggregates are deeply involved in the pathogenesis, there have been many attempts to demonstrate the mechanism of the aggregation and its potential causative factors including post-translational modifications (PTMs). Although no concrete conclusions have been made based on the previous study results, growing evidence suggests that modifications such as phosphorylation and ubiquitination can alter α-syn characteristics to have certain effects on the aggregation process in PD; either facilitating or inhibiting fibrillization. In the present work, we reviewed studies showing the significant impacts of PTMs on α-syn aggregation. Furthermore, the PTMs modulating α-syn aggregation-induced cell death have been discussed. [BMB Reports 2022; 55(7): 323-335].

Topics: alpha-Synuclein; Humans; Lewy Bodies; Parkinson Disease; Phosphorylation; Protein Processing, Post-Translational

Parkinson's disease is a neurodegenerative condition initially characterized by the presence of tremor, muscle stiffness and impaired balance, with the deposition of insoluble protein aggregates in Lewy's Bodies the histopathological hallmark of the disease. Although different gene variants are linked to Parkinson disease, mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are one of the most frequent causes of Parkinson's disease related to genetic mutations. LRRK2 toxicity has been mainly explained by an increase in kinase activity, but alternative mechanisms have emerged as underlying causes for Parkinson's disease, such as the imbalance in LRRK2 homeostasis and the involvement of LRRK2 in aggregation and spreading of α-synuclein toxicity. In this review, we recapitulate the main LRRK2 pathological mutations that contribute to Parkinson's disease and the different cellular and therapeutic strategies devised to correct LRRK2 homeostasis. In this review, we describe the main cellular control mechanisms that regulate LRRK2 folding and aggregation, such as the chaperone network and the protein-clearing pathways such as the ubiquitin-proteasome system and the autophagic-lysosomal pathway. We will also address the more relevant strategies to modulate neurodegeneration in Parkinson's disease through the regulation of LRRK2, using small molecules or LRRK2 silencing.

Topics: alpha-Synuclein; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lysosomes; Mutation; Parkinson Disease; Proteostasis

Microglia are the primary resident immune cells of the central nervous system. Neuropathological reports have identified augmented microglial activation in brains of patients with neurodegenerative disorders including Parkinson's disease (PD). Extensive research over the years has strengthened the current view on microglia as a player in the pathogenesis of PD and other α-synucleinopathies. In this review, we summarize key findings of the recent three years on microglia in PD with specific relevance to understanding its heterogeneity, dual nature, and specific interactions with pathological α-synuclein strains to mediate its clearance and spreading. This review provides evidence on the relevance of microglia as a putative biomarker and therapeutic target in PD and related disorders.

Topics: alpha-Synuclein; Brain; Humans; Microglia; Neurodegenerative Diseases; Parkinson Disease

Inflammation has increasingly become a focus of study in regards to Parkinson's disease (PD). Moreover, both central and peripheral sources of inflammation have been implicated in the pathogenesis of PD. Central inflammation consisting of activated microglia, astroglia, and T cell responses within the PD central nervous system; and peripheral inflammation referring to activated innate cells and T cell signaling in the enteric nervous system, gastrointestinal tract, and blood. This review will highlight important work that further implicates central and peripheral inflammation in playing a role in PD. We also discuss how these two distant inflammations appear related and how that may be mediated by autoantigenic responses to α-syn.

Topics: alpha-Synuclein; Enteric Nervous System; Humans; Immunity; Inflammation; Microglia; Parkinson Disease

Lysosomes have a critical role in maintaining normal cellular homeostasis mediated by their involvement in secretion, plasma membrane repair, cell signaling and energy metabolism. Lysosomal storage disorders (LSDs) are a group of approximately 50 rare disorders caused by lysosomal dysfunction that occur due to mutations in a gene of a lysosomal protein. Gaucher disease (GD), an autosomal recessive disorder and one of the most common LSDs, is caused by the deficiency of the lysosomal enzyme acid-β-glucocerebrosidase (GCase), due to biallelic mutations in the GBA1 gene. Reduced GCase activity leads to the accumulation of glucosylceramide (GlcCer), which is deacylated by lysosomal acid ceramidase to a toxic metabolite, glucosylshpingosine (GlcSph). Most GBA1 variants are recognized as misfolded in the ER, where the retention for refolding attempts initiates stress and activates the stress response known as the Unfolded Protein Response (UPR). The distinct clinical subtypes of GD are based on whether there is primary involvement of the central nervous system. Type 1 GD (GD1) is the nonneuropathic type, however, the recent recognition of the association of GD with the development of parkinsonism defies this classification. Patients with GD1 and carriers of GBA1 mutations are at risk for the development of parkinsonian manifestations. Parkinson disease (PD), the second most prevalent neurodegenerative disease, culminates in a movement disorder with the premature death of the patients. In PD and related disorders, collectively called synucleinopathies, the hallmark pathology is α-synuclein positive aggregates referred to as Lewy bodies or Lewy neurites and the death of dopaminergic neurons. While PD is mostly sporadic, in ∼5-10% of cases, the disease results from pathogenic variants in a growing number of genes. The most common genetic cause of PD is mutations in GBA1. Two mechanisms have been proposed for this link: (A) a "gain of function" mechanism, in which mutant GCase (protein) contributes to aggregate formation and to the development of PD, and the (B) "haploinsufficiency" ("loss of function") model, suggesting that one normal GBA1 allele is insufficient to carry adequate GCase activity and functional deficiency of GCase impedes α-synuclein metabolism. Lysosomal dysfunction, compromised autophagy and mitophagy further enhance the accumulation of α-synuclein, which results in the development of PD pathology. The present review will elaborate on the biology

Topics: alpha-Synuclein; Gaucher Disease; Glucosylceramidase; Humans; Lysosomes; Mutation; Neurodegenerative Diseases; Parkinson Disease

Neuroinflammation has become a well-accepted pathologic hallmark of Parkinson's disease (PD). However, it remains unclear whether inflammation, triggered by α-syn aggregation and/or degeneration, contributes to the progression of the disease. Studies examining neuroinflammation in PD are unable to distinguish between Lewy body-associated inflammation and degeneration-associated inflammation, as both pathologies are present simultaneously. Intrastriatal and intranigral injections of alpha-synuclein (α-syn) preformed fibrils (PFFs) results in two distinct pathologic phases: Phase 1: The accumulation and peak formation of α-syn inclusions in nigrostriatal system and, Phase 2: Protracted dopaminergic neuron degeneration. In this review we summarize the current understanding of neuroinflammation in the α-syn PFF model, leveraging the distinct Phase 1 aggregation phase and Phase 2 degeneration phase to guide our interpretations. Studies consistently demonstrate an association between pathologic α-syn aggregation in the substantia nigra (SN) and activation of the innate immune system. Further, major histocompatibility complex-II (MHC-II) antigen presentation is proportionate to inclusion load. The α-syn aggregation phase is also associated with peripheral and adaptive immune cell infiltration to the SN. These findings suggest that α-syn like aggregates are immunogenic and thus have the potential to contribute to the degenerative process. Studies examining neuroinflammation during the neurodegenerative phase reveal elevated innate, adaptive, and peripheral immune cell markers, however limitations of single time point experimental design hinder interpretations as to whether this neuroinflammation preceded, or was triggered by, nigral degeneration. Longitudinal studies across both the aggregation and degeneration phases of the model suggest that microglial activation (MHC-II) is greater in magnitude during the aggregation phase that precedes degeneration. Overall, the consistency between neuroinflammatory markers in the parkinsonian brain and in the α-syn PFF model, combined with the distinct aggregation and degenerative phases, establishes the utility of this model platform to yield insights into pathologic events that contribute to neuroinflammation and disease progression in PD.

Topics: alpha-Synuclein; Humans; Inflammation; Lewy Bodies; Parkinson Disease; Substantia Nigra

Parkinson's disease (PD) is currently considered a multisystemic disorder rather than a pure brain disease, in line with the multiple hit hypothesis from Braak. However, despite increasing evidence that the pathology might originate in the periphery, multiple unknown aspects and contradictory data on the pathological processes taking place in the periphery jeopardize the interpretation and therapeutic targeting of PD. Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been widely linked with familial and sporadic PD cases. However, the actual role of LRRK2 in PD pathophysiology is far from understood. There is evidence that LRRK2 may be involved in alpha-synuclein (α-synuclein) pathology and immune cell regulation, but it has also been associated with inflammatory diseases such as inflammatory bowel disease, tuberculosis, leprosy, and several other bacterial infections. In this review, we focus on the different roles of LRRK2 in the periphery. More specifically, we discuss the involvement of LRRK2 in the propagation of α-synuclein pathology and its regulatory role in peripheral inflammation. A deeper understanding of the multidimensional functions of LRRK2 will pave the way for more accurate characterization of PD pathophysiology and its association with other inflammatory diseases.

Topics: alpha-Synuclein; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disorder that alters either motor or non-motor activities. Dopamine-based medications can help alleviate symptoms at an early stage, but the disease worsens due to fewer neuroprotective drugs. PD's pathogenic mechanism involves α-synuclein accumulations, lipid peroxidation damage, iron deposition, and enhanced oxidative stress. An iron-dependent method of programmed cell death known as ferroptosis, which results from the dangerous accumulation of lipid peroxides, is similar to PD. The interesting fact is that α-synuclein has been functionally connected to iron or lipid metabolism, suggesting that dysregulated α-syn may interact with other PD clinical traits associated with ferroptosis. Treatments aimed at restoring dopamine levels in the brain are already available; however, they only alleviate symptoms and do not stop the progression of neurodegeneration. Ferroptosis-related mechanisms that could be targeted for treatment will be discussed in this review. Researchers have found that anti-ferroptosis molecules such as iron chelators and anti-oxidants protect the brains of PD animal models and humans. The ferroptosis pathway in PD and the treatment prospects of addressing the molecular pathways engaged in ferroptosis are both examined in this review.

Topics: alpha-Synuclein; Animals; Dopamine; Dopamine Agents; Ferroptosis; Humans; Iron; Parkinson Disease

Parkinson's disease (PD) is the second-most-common neurodegenerative disease characterized by motor and non-motor dysfunctions, which currently affects about 10 million people worldwide. Gradual death and progressive loss of dopaminergic neurons in the pars compacta region of substantia nigra result in striatal dopamine deficiency in PD. Specific mutation with further aggregation of α-synuclein in the intraneuronal inclusion bodies is considered the neuropathological hallmark of this disease. PD is often associated with various organelle dysfunctions inside a dopaminergic neuron, including mitochondrial damage, proteasomal impairment, and production of reactive oxygen species, thus causing subsequent neuronal death. Apart from several genetic and non-genetic risk factors, emerging research establishes an association between cardiovascular diseases, including coronary heart disease, myocardial infarction, congestive heart failure, and ischemic stroke with PD. The majority of these cardiovascular diseases have an origin from atherosclerosis, where endothelial dysfunction following thrombus formation is significantly regulated by blood platelet. This non-nucleated cell fragment expresses not only neuron-specific molecules and receptors but also several PD-specific biomarkers such as α-synuclein, parkin, PTEN-induced kinase-1, tyrosine hydroxylase, dopamine transporter, thus making platelet a suitable peripheral model for PD. Besides its similarity with a dopaminergic neuron, platelet structural alterations, as well as functional abnormalities, are also evident in PD. However, the molecular mechanism behind platelet dysfunction is still elusive and quite controversial. This state-of-the-art review describes the detailed mechanism of platelet impairment in PD, addressing the novel platelet-associated therapeutic drug candidates for plausible PD management.

Topics: alpha-Synuclein; Blood Platelets; Cardiovascular Diseases; Dopaminergic Neurons; Humans; Neurodegenerative Diseases; Parkinson Disease; Precision Medicine; Substantia Nigra

Parkinson's disease (PD) is conventionally described as an α-synuclein aggregation disorder, defined by Lewy bodies and neurites, and mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common autosomal dominant cause of PD. However, LRRK2 mutations may be associated with diverse pathologies in patients with Parkinson's syndrome including tau pathology resembling progressive supranuclear palsy (PSP). The recent discovery that variation at the LRRK2 locus is associated with the progression of PSP highlights the potential importance of LRRK2 in tauopathies. Here, we review the emerging evidence and discuss the potential impact of LRRK2 dysfunction on tau aggregation, lysosomal function, and endocytosis and exocytosis.

Topics: alpha-Synuclein; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease; Tauopathies

Parkinson's disease (PD) pathology is the most common motor neurodegenerative disease that occurs due to the progressive degeneration of dopaminergic neurons of the nigrostriatal pathway of the brain. The histopathological hallmark of the disease is fibrillary aggregate called Lewy bodies which majorly contain α-synuclein, suggesting the critical implication of diminished protein degradation mechanisms in disease pathogenesis. This α-synuclein-containing Lewy bodies are evident in both experimental models as well as in postmortem PD brain and are speculated to be pathogenic but still, the lineal association between these aggregates and the complexity of disease pathology is not yet well established and needs further attention. However, it has been reported that α-synuclein aggregates have consorted with the declined proteasome and lysosome activities. Therefore, in this review, we reappraise intracellular protein degradation mechanisms during PD pathology. This article focused on the findings of the last two decades suggesting the implications of protein degradation mechanisms in disease pathogenesis and based on shreds of evidence, some of the approaches are also suggested which may be adopted to find out the novel therapeutic targets for the management of PD patients.

Topics: alpha-Synuclein; Humans; Neurodegenerative Diseases; Parkinson Disease; Proteasome Endopeptidase Complex; Proteolysis

The development of disease-modifying drugs and differential diagnostic agents is an urgent medical need in Parkinson's disease. Despite the complex pathophysiological pathway, the misfolding of alpha-synuclein has been identified as a putative biomarker for detecting the onset and progression of the neurodegeneration associated with Parkinson's disease. Identifying the most appropriate alpha-synuclein-based diagnostic modality with clinical translation will revolutionize the diagnosis of Parkinson's. Likewise, molecules that target alpha-synuclein could alter the disease pathway that leads to Parkinson's and may serve as first-in class therapeutics compared to existing treatment options such as levodopa and dopamine agonist that do not necessarily modify the disease pathway. Notwithstanding the promising benefits that alpha-synuclein presents to therapeutics and diagnostics development for Parkinson's disease, finding ways to address potential challenges such as inadequate preclinical models, safety and efficacy will be paramount to achieving clinical translation. In this comprehensive review paper, we described the role of alpha-synuclein in the pathogenesis of Parkinson's disease, as well as how its structure and function relationship delineate disease onset and progression. We further discussed different alpha-synuclein-based diagnostic modalities including biomolecular assays and molecular imaging. Finally, we presented current small molecules and biologics that are being developed as disease-modifying drugs or positron emission tomography imaging probes for Parkinson's disease.

Topics: alpha-Synuclein; Biological Products; Biomarkers; Dopamine Agonists; Humans; Levodopa; Parkinson Disease

Chronic sterile inflammation and persistent immune activation is a prominent pathological feature of Parkinson's disease (PD). Inflammasomes are multi-protein intracellular signaling complexes which orchestrate inflammatory responses in immune cells to a diverse range of pathogens and host-derived signals. Widespread inflammasome activation is evident in PD patients at the sites of dopaminergic degeneration as well as in blood samples and mucosal biopsies. Inflammasome activation in the nigrostriatal system is also a common pathological feature in both neurotoxicant and α-synuclein models of PD where dopaminergic degeneration occurs through distinct mechanisms. The NLRP3 (NLR Family Pyrin Domain Containing 3) inflammasome has been shown to be the primary driver of inflammatory neurotoxicity in PD and other neurodegenerative diseases. Chronic NLRP3 inflammasome activation is triggered by pathogenic misfolded α-synuclein aggregates which accumulate and spread over the disease course in PD. Converging lines of evidence suggest that blocking inflammasome activation could be a promising therapeutic strategy for disease modification, with both NLRP3 knockout mice and CNS-permeable pharmacological inhibitors providing robust neuroprotection in multiple PD models. This review summarizes the current evidence and knowledge gaps around inflammasome activation in PD, the pathological mechanisms by which persistent inflammasome activation can drive dopaminergic degeneration and the therapeutic opportunities for disease modification using NLRP3 inhibitors.

Topics: alpha-Synuclein; Animals; Dopamine; Dopaminergic Neurons; Inflammasomes; Inflammation; Mice; Mice, Knockout; Microglia; NLR Family, Pyrin Domain-Containing 3 Protein; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disorder that gradually develops over time in a progressive manner. The main culprit behind the disease pathology is dopaminergic deficiency in Substantia nigra Pars Compacta (SNpc) due to neuronal degeneration. However, there are other factors that are not only associated with it but also somehow responsible for inception of pathology. Metabolic syndrome is one such risk factor for PD. Metabolic syndrome is a cluster of diseases mainly including diabetes, hypertension, obesity, and hyperlipidemia which pose a risk for developing cardiovascular disorders. All of these disorders have their own pathological pathways that intertwine with PD pathology. This leads to alpha-synuclein aggregation, neuroinflammation, mitochondrial dysfunction, and oxidative stress which are facets in initiating PD pathology. Although few reports are available, this area is underexplored and has contradictory views. Hence, further studies are needed in order to establish a definite relationship between PD and metabolic syndrome. In this review, we aim to elucidate the molecular mechanisms to confirm the association between them and pave the way for potential repurposing of therapies.

Topics: alpha-Synuclein; Dopaminergic Neurons; Humans; Metabolic Syndrome; Oxidative Stress; Parkinson Disease; Pars Compacta

Dysregulation of innate and adaptive immunity can lead to alpha-synuclein (α-syn) misfolding, aggregation, and post-translational modifications in Parkinson's disease (PD). This process is driven by neuroinflammation and oxidative stress, which can contribute to the release of neurotoxic oligomers that facilitate dopaminergic neurodegeneration. Strategies that promote vaccines and antibodies target the clearance of misfolded, modified α-syn, while gene therapy approaches propose to deliver intracellular single chain nanobodies to mitigate α-syn misfolding, or to deliver neurotrophic factors that support neuronal viability in an otherwise neurotoxic environment. Additionally, transformative immune responses provide potential targets for PD therapeutics. Anti-inflammatory drugs represent one strategy that principally affects innate immunity. Considerable research efforts have focused on transforming the balance of pro-inflammatory effector T cells (Teffs) to favor regulatory T cell (Treg) activity, which aims to attenuate neuroinflammation and support reparative and neurotrophic homeostasis. This approach serves to control innate microglial neurotoxic activities and may facilitate clearance of α-syn aggregates accordingly. More recently, changes in the intestinal microbiome have been shown to alter the gut-immune-brain axis leading to suppressed leakage of bacterial products that can promote peripheral inflammation and α-syn misfolding. Together, each of the approaches serves to interdict chronic inflammation associated with disordered immunity and neurodegeneration. Herein, we examine research strategies aimed at improving clinical outcomes in PD.

Topics: alpha-Synuclein; Humans; Inflammation; Nerve Growth Factors; Parkinson Disease; Single-Domain Antibodies

Parkinson's disease (PD) is the second most common neurodegenerative disorder, classically associated with extensive loss of dopaminergic neurons of the substantia nigra pars compacta. The hallmark of the disease is the accumulation of pathogenic conformations of the presynaptic protein, α-synuclein (αSyn), and the formation of intraneuronal protein aggregate inclusions. Neurodegeneration of dopamine neurons leads to a prominent dopaminergic deficiency in the basal ganglia, responsible for motor disturbances. However, it is now recognized that the disease involves more widespread neuronal dysfunction, leading to early and late non-motor symptoms. The development of in vitro systems based on the differentiation of human-induced pluripotent stem cells provides us the unique opportunity to monitor alterations at the cellular and molecular level throughout the differentiation procedure and identify perturbations that occur early, even at the neuronal precursor stage. Here we aim to identify whether p.A53T-αSyn induced disturbances at the molecular level are already present in neural precursors. Towards this, we present data from transcriptomics analysis of control and p.A53T-αSyn NPCs showing altered expression in transcripts involved in axon guidance, adhesion, synaptogenesis, ion transport, and metabolism. The comparative analysis with the transcriptomics profile of p.A53T-αSyn neurons shows both distinct and overlapping pathways leading to neurodegeneration while meta-analysis with transcriptomics data from both neurodegenerative and neurodevelopmental disorders reveals that p.A53T-pathology has a significant overlap with the latter category. This is the first study showing that molecular dysregulation initiates early at the p.A53T-αSyn NPC level, suggesting that synucleinopathies may have a neurodevelopmental component.

Topics: alpha-Synuclein; Dopamine; Dopaminergic Neurons; Humans; Induced Pluripotent Stem Cells; Parkinson Disease; Synucleinopathies

The pathological accumulation of alpha-synuclein governs the pathogenesis of neurodegenerative disorders, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, collectively termed alpha-synucleinopathies. Alpha-synuclein can be released in the extracellular space, partly via exosomes, and this extracellular protein pool may contribute to disease progression by facilitating the spread of pathological alpha-synuclein or activating immune cells. The content of exosomes depends on their origin and includes specific proteins, lipids, functional mRNAs and various non-coding RNAs. Given their ability to mediate intercellular communication via the transport of multilevel information, exosomes are considered to be transporters of toxic agents. Beyond neurons, glial cells also release exosomes, which may contain inflammatory molecules and this glia-to-neuron or neuron-to-glia transmission of exosomal alpha-synuclein may contribute to the propagation of pathology and neuroinflammation throughout the brain. In addition, as their content varies as per their originating and recipient cells, these vesicles can be utilized as a diagnostic biomarker for early disease detection, whereas targeted exosomes may be used as scaffolds to deliver therapeutic agents into the brain. This review summarizes the current knowledge regarding the role of exosomes in the progression of alpha-synuclein-related pathology and their potential use as biomarkers and nanotherapeutics in alpha-synucleinopathies.

Topics: alpha-Synuclein; Exosomes; Humans; Lewy Bodies; Parkinson Disease; Synucleinopathies

α-Synuclein (αS) is remarkable for both its extensive conformational plasticity and pathologic prion-like properties. Physiologically, αS may populate disordered monomeric, helically folded tetrameric, or membrane-bound oligomeric states. Pathologically, αS may assemble into toxic oligomers and subsequently fibrils, the prion-like transmission of which is implicated in a class of neurodegenerative disorders collectively termed α-synucleinopathies. Notably, αS does not adopt a single "amyloid fold", but rather exists as structurally distinct amyloid-like conformations referred to as "strains". The inoculation of animal models with different strains induces distinct pathologies, and emerging evidence suggests that the propagation of disease-specific strains underlies the differential pathologies observed in patients with different α-synucleinopathies. The characterization of αS strains has provided insight into the structural basis for the overlapping, yet distinct, symptoms of Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. In this review, we first explore the physiological and pathological differences between conformational states of αS. We then discuss recent studies on the influence of micro-environmental factors on αS species formation, propagation, and the resultant pathological characteristics. Lastly, we review how an understanding of αS conformational properties has been translated to emerging strain amplification technologies, which have provided further insight into the role of specific strains in distinct α-synucleinopathies, and show promise for the early diagnosis of disease.

Topics: alpha-Synuclein; Animals; Multiple System Atrophy; Parkinson Disease; Prions; Synucleinopathies

The clinical differentiation between multiple system atrophy (MSA), Parkinson's disease (PD), dementia with Lewy bodies (DLB), as well as the distinction between these synucleinopathies from other neurodegenerative disorders can be challenging, particularly at early disease stages or when the presentation is atypical. That is also true for predicting the fate of patients with limited or prodromal forms of synucleinopathies such as pure autonomic failure (PAF) or idiopathic REM-sleep behavior disorder (iRBD) which are known to be at risk of developing MSA, PD, or DLB. After discussing current classification concepts of the synucleinopathies, this invited mini-review reflects on two recently described and validated spinal fluid biomarkers, namely neurofilament light chain (NfL) and α-synuclein oligomers detected by protein aggregation assays, that have shown great promise not only as markers differentiating MSA from the Lewy-body synucleinopathies but also as markers that predict future phenoconversion to MSA among patients with PAF. Discussed are the strengths and limitations of these markers, and how they appear to complement each other nicely as a biomarker panel, enhancing the specificity of one of these markers, yet adding further robustness and simplicity to a marker that is technically rather challenging. The review concludes with thoughts on potential next steps in the development of fluid biomarkers in this rapidly emerging field.

Topics: alpha-Synuclein; Biomarkers; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Pure Autonomic Failure; REM Sleep Behavior Disorder; Synucleinopathies

Parkinson's disease (PD) is an ageing disorder with deterioration of dopamine neurons which leads to motor complications like tremor, stiffness, slow movement and postural disturbances. In PD, both genetics as well as environmental factors both play a major role in causing the pathogenesis. Though there are surfeit of risk factors involved in PD occurrence, till now there is lack of an exact causative agent as a risk for PD with confirmative findings. The role of heavy metals reported to be a significant factor in PD pathogenesis. Heavy metal functions in cell maintenance but growing pieces of evidences reported to cause dyshomeostasis with increased PD rate. Metals disturb the molecular processes and results in oxidative stress, DNA damage, mitochondrial dysfunction, and apoptosis. The present review elucidates the role of cobalt, nickel, mercury, chromium, thallium metals in α-synuclein aggregation and its involvement in blood brain barrier flux. Also, the review explains the plausible role of aforementioned metals with a mechanistic approach and therapeutic recommendations in PD.

Topics: alpha-Synuclein; Chromium; Cobalt; Humans; Mercury; Metals, Heavy; Nickel; Parkinson Disease; Thallium

Parkinson disease (PD) is the second most common neurodegenerative disease, and the most common synucleinopathy, as alpha-synuclein (α-syn), a prion-like protein, plays an important pathophysiologic role in its onset and progression. Although neuropathologic changes begin many years before the onset of motor manifestations, diagnosis still relies on the identification of the motor symptoms, which hinders to formulate an early diagnosis. Because α-syn misfolding and aggregation precede clinical manifestations, the possibility to identify these phenomena in patients with PD would allow us to recognize the disease at the earliest, premotor phases, as a consequence of the transition from a clinical to a molecular diagnosis. Seed amplification assays (SAAs) are a group of techniques that currently support the diagnosis of prion subacute encephalopathies, namely Creutzfeldt-Jakob disease. These techniques enable the detection of minimal amounts of prions in CSF and other matrices of affected patients. Recently, SAAs have been successfully applied to detect misfolded alpha-synuclein (α-syn) in CSF, olfactory mucosa, submandibular gland biopsies, skin, and saliva of patients with Parkinson disease (PD) and other synucleinopathies. In these categories, they can differentiate PD and dementia with Lewy bodies (DLBs) from control subjects, even in the prodromal stages of the disease. In differential diagnosis, SAAs satisfactorily differentiated PD, DLB, and multiple system atrophy (MSA) from nonsynucleinopathy parkinsonisms. The kinetic analysis of the SAA fluorescence profiles allowed the identification of synucleinopathy-dependent α-syn fibrils conformations, commonly referred to as strains, which have demonstrated diagnostic potential in differentiating among synucleinopathies, especially between Lewy body diseases (LBDs) (PD and DLB) and MSA. In front of these highly promising data, which make the α-syn seeding activity detected by SAAs as the most promising diagnostic biomarker for synucleinopathies, there are still preanalytical and analytical issues, mostly related to the assay standardization, which need to be solved. In this review, we discuss the key findings supporting the clinical application of α-syn SAAs to identify PD and other synucleinopathies, the unmet needs, and future perspectives.

Topics: alpha-Synuclein; Humans; Kinetics; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Prions; Synucleinopathies

The discovery of glucocerebrosidase (GBA1) mutations as the greatest numerical genetic risk factor for the development of Parkinson disease (PD) resulted in a paradigm shift within the research landscape. Efforts to elucidate the mechanisms behind GBA1-associated PD have highlighted shared pathways in idiopathic PD including the loss and gain-of-function hypotheses, endoplasmic reticulum stress, lipid metabolism, neuroinflammation, mitochondrial dysfunction and altered autophagy-lysosomal pathway responsible for degradation of aggregated and misfolded a-synuclein. GBA1-associated PD exhibits subtle differences in phenotype and disease progression compared to idiopathic counterparts notably an earlier age of onset, faster motor decline and greater frequency of non-motor symptoms (which also constitute a significant aspect of the prodromal phase of the disease). GBA1-targeted therapies have been developed and are being investigated in clinical trials. The most notable are Ambroxol, a small molecule chaperone, and Venglustat, a blood-brain-barrier-penetrant substrate reduction therapy agent. It is imperative that further studies clarify the aetiology of GBA1-associated PD, enabling the development of a greater abundance of targeted therapies in this new era of precision medicine.

Topics: alpha-Synuclein; Glucosylceramidase; Humans; Lysosomes; Mutation; Parkinson Disease

It is well known that B lymphocytes differentiate into plasma cells that produce antibodies. B cells also perform a number of less well-known roles including antigen presentation, regulation of T cells and innate immune cells, cytokine production, and maintenance of subcapsular sinus macrophages. Given that there is clear evidence of inflammation in Parkinson's disease (PD) both in the central nervous system and in the periphery, it is almost certain that B lymphocytes are involved. This involvement is likely to be complicated given the variety of roles B cells play via a number of distinct subsets. They have received less attention to date than their counterparts, T cells, and monocytes. B lymphocytes are decreased in PD overall with some limited evidence that this may be driven by a decrease in regulatory subsets. There is also evidence that regulatory B cells are protective in PD. There is evidence for a role played by antibodies to alpha-synuclein in PD with a possible increase in early disease. There are many exciting potential future avenues for further exploration of the role of B lymphocytes including improving our understanding of the role of meningeal and calvarial (skull bone marrow) based B cells in health and disease, the use of larger, well phenotyped clinical cohorts to understand changes in peripheral and cerebrospinal fluid B cells over time and the potential application of B cell targeted therapies in PD.

Topics: alpha-Synuclein; B-Lymphocytes; Central Nervous System; Cytokines; Humans; Parkinson Disease

Neuroinflammation is an inflammatory process in the central nervous system (CNS), in addition to being one of the main features of Alzheimer's disease (AD) and Parkinson's disease (PD). Microglia are known for their immune functions and have multiple reactive phenotypes related to the types of stages involving neurodegenerative diseases. Depending on the state of activation of microglia in the CNS, it can be neuroprotective or neurotoxic. In this context, AD is a neurodegenerative and neuroinflammatory disease characterized by the deposition of beta-amyloid plaques, formation of fibrillar tangles of tau protein, and loss of neurons due to neurotoxic activation of microglia. However, PD is characterized by the loss of dopaminergic neurons in the substantia nigra and accumulation of alpha-synuclein in the cortical regions, spinal cord, and brain stem, which occurs by microglial activation, contributing to the neuroinflammatory process. In this aspect, the activation of microglia in both pathologies triggers high levels of inflammatory markers, such as interleukins, and causes the neuroinflammatory process of the diseases. Thus, physical exercise is pointed out as neuroprotective, as it can act to strengthen neurogenesis and reduce the inflammatory process. Therefore, the present review addresses the neuroprotective effect of microglia after different types of physical exercise protocols and evaluates the activity and effects of inflammatory and anti-inflammatory parameters and mechanisms of AD and PD. This review will discuss the anti-inflammatory effects of physical exercise through microglia activation with neuroprotective activity and the role of pro-and anti-inflammatory cytokines in AD and PD.

Topics: alpha-Synuclein; Alzheimer Disease; Anti-Inflammatory Agents; Cytokines; Dopaminergic Neurons; Exercise; Humans; Inflammation Mediators; Microglia; Neuroprotective Agents; Parkinson Disease; tau Proteins

Parkinson's disease (PD) is the second most common neurodegenerative disease, with two main pathological features: misfolded α-synuclein protein accumulation and neurodegeneration. Inflammation has recently been identified as a contributor to a cascade of events that may aggravate PD pathology. Inflammasomes, a group of intracellular protein complexes, play an important role in innate immune responses to various diseases, including infection. In PD research, accumulating evidence suggests that α-synuclein aggregations may activate inflammasomes, particularly the nucleotide-binding oligomerization domain-leucine-rich repeat-pyrin domain-containing 3 (NLRP3) type, which exacerbates inflammation in the central nervous system by secreting proinflammatory cytokines like interleukin (IL)-18 and IL-1β. Afterward, activated NLRP3 triggers local microglia and astrocytes to release additional IL-1β. In turn, the activated inflammatory process may contribute to additional α-synuclein aggregation and cell loss. This review summarizes current research evidence on how the NLRP3 inflammasome contributes to PD pathogenesis, as well as potential therapeutic strategies targeting the NLRP3 inflammasome in PD.

Topics: alpha-Synuclein; Cytokines; Humans; Inflammasomes; Inflammation; Leucine; Neurodegenerative Diseases; NLR Family, Pyrin Domain-Containing 3 Protein; Nucleotides; Parkinson Disease

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.

Topics: alpha-Synuclein; Epigenome; Frontal Lobe; Humans; Lewy Bodies; Lewy Body Disease; Methylation; Parkinson Disease

The expression of Hemoglobin (Hb) is not restricted to erythrocytes but is also present in neurons. Hb is selectively enriched in vulnerable mesencephalic dopaminergic neurons of Parkinson's disease (PD) instead of resistant neurons. Controversial results of neuronal Hb levels have been reported in postmortem brains of PD patients: although neuronal Hb levels may decline in PD patients, elderly men with higher Hb levels have an increased risk of developing PD. α-synuclein, a key protein involved in PD pathology, interacts directly with Hb protein and forms complexes in erythrocytes and brains of monkeys and humans. These complexes increase in erythrocytes and striatal cytoplasm, while they decrease in striatal mitochondria with aging. Besides, the colocalization of serine 129-phosphorylated (Pser129) α-synuclein and Hb β chains have been found in the brains of PD patients. Several underlying molecular mechanisms involving mitochondrial homeostasis, α-synuclein accumulation, iron metabolism, and hormone-regulated signaling pathways have been investigated to assess the relationship between neuronal Hb and PD development. The formation of fibrils with neuronal Hb in various neurodegenerative diseases may indicate a common fibrillization pathway and a widespread target that could be applied in neurodegeneration therapy.

Topics: Aged; alpha-Synuclein; Dopaminergic Neurons; Hemoglobins; Humans; Male; Mesencephalon; Parkinson Disease

About 10% of the adult population is living with type 2 diabetes mellitus (T2DM) and 1% of the population over 60 years of age is suffering from Parkinson's disease (PD). A school of thought firmly believes that T2DM, an age-related disease, augments PD risk. Such relationship is reflected from the severity of PD symptoms in drug naive subjects possessing T2DM. Onset of Parkinsonian feature in case controls possessing T2DM corroborates the role of hyperglycemia in PD. A few cohort, meta-analysis and animal studies have shown an increased PD risk owing to insulin resistance. High fat diet and role of insulin signaling in the regulation of sugar metabolism, oxidative stress, α-synuclein aggregation and accumulation, inflammatory response and mitochondrial function in PD models and sporadic PD further connect the two. Although little is reported about the implication of PD in hyperglycemia and T2DM, a few studies have also contradicted. Ameliorative effect of anti-diabetic drugs on Parkinsonian symptoms and vague outcome of anti-PD medications in T2DM patients also suggest a link. The article reviews the literature supporting augmented risk of one by the other, analysis of proof of the concept, facts, challenges, future possibilities and standpoint on the subject.

Topics: alpha-Synuclein; Animals; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Insulin; Parkinson Disease

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease, globally. Dopaminergic neuron degeneration in substantia nigra pars compacta and aggregation of misfolded alpha-synuclein are the PD hallmarks, accompanied by motor and non-motor symptoms. Several viruses have been linked to the appearance of a post-infection parkinsonian phenotype. Coronavirus disease 2019 (COVID-19), caused by emerging severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, has evolved from a novel pneumonia to a multifaceted syndrome with multiple clinical manifestations, among which neurological sequalae appear insidious and potentially long-lasting. Exosomes are extracellular nanovesicles bearing a complex cargo of active biomolecules and playing crucial roles in intercellular communication under pathophysiological conditions. Exosomes constitute a reliable route for misfolded protein transmission, contributing to PD pathogenesis and diagnosis. Herein, we summarize recent evidence suggesting that SARS-CoV-2 infection shares numerous clinical manifestations and inflammatory and molecular pathways with PD. We carry on hypothesizing that these similarities may be reflected in exosomal cargo modulated by the virus in correlation with disease severity. Travelling from the periphery to the brain, SARS-CoV-2-related exosomal cargo contains SARS-CoV-2 RNA, viral proteins, inflammatory mediators, and modified host proteins that could operate as promoters of neurodegenerative and neuroinflammatory cascades, potentially leading to a future parkinsonism and PD development.

Topics: alpha-Synuclein; Cell Communication; COVID-19; Humans; Neurodegenerative Diseases; Parkinson Disease; Parkinsonian Disorders; RNA, Viral; SARS-CoV-2

The therapeutic strategies currently available for neurodegenerative diseases such as Parkinson's disease target only the symptoms of the disease. Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy can be summarized as synucleinopathies, as they are all characterized by the aggregation and accumulation of alpha-synuclein (α-syn) in the brain. Targeting α-syn by its formation and progression opens a new and promising disease-modifying therapeutic strategy. Thus, several distinct immunotherapeutic approaches are currently being evaluated in clinical trials. The objective of this article is to review, from a biological perspective, the most important properties of these passive and active immunotherapies to point out their relevance and suitability for the treatment of synucleinopathies.

Topics: alpha-Synuclein; Humans; Multiple System Atrophy; Parkinson Disease; Synucleinopathies; Vaccination

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human coronavirus (HCoV) that has created a pandemic situation worldwide as COVID-19. This virus can invade human cells via angiotensin-converting enzyme 2 (ACE2) receptor-based mechanisms, affecting the human respiratory tract. However, several reports of neurological symptoms suggest a neuroinvasive development of coronavirus. SARS-CoV-2 can damage the brain via several routes, along with direct neural cell infection with the coronavirus. The chronic inflammatory reactions surge the brain with proinflammatory elements, damaging the neural cells, causing brain ischemia associated with other health issues. SARS-CoV-2 exhibited neuropsychiatric and neurological manifestations, including cognitive impairment, depression, dizziness, delirium, and disturbed sleep. These symptoms show nervous tissue damage that enhances the occurrence of neurodegenerative disorders and aids dementia. SARS-CoV-2 has been seen in brain necropsy and isolated from the cerebrospinal fluid of COVID-19 patients. The associated inflammatory reaction in some COVID-19 patients has increased proinflammatory cytokines, which have been investigated as a prognostic factor. Therefore, the immunogenic changes observed in Parkinson's and Alzheimer's patients include their pathogenetic role. Inflammatory events have been an important pathophysiological feature of neurodegenerative diseases (NDs) such as Parkinson's and Alzheimer's. The neuroinflammation observed in AD has exacerbated the A

Topics: alpha-Synuclein; Alzheimer Disease; COVID-19; Humans; Parkinson Disease; Peptidyl-Dipeptidase A; SARS-CoV-2

Parkinson's disease (PD) is one of the most common neurological diseases, next only to Alzheimer's disease (AD) in terms of prevalence. It afflicts about 2-3% of individuals over 65 years old. The etiology of PD is unknown and several environmental and genetic factors are involved. From a pathological point of view, PD is characterized by the loss of dopaminergic neurons in the substantia nigra, which causes the abnormal accumulation of α-synuclein (α-syn) (a component of Lewy bodies), which subsequently interact with heat shock proteins (HSPs), leading to apoptosis. Apoptosis is a vital pathway for establishing homeostasis in body tissues, which is regulated by pro-apoptotic and anti-apoptotic factors. Recent findings have shown that HSPs, especially HSP27 and HSP70, play a pivotal role in regulating apoptosis by influencing the factors involved in the apoptosis pathway. Moreover, it has been reported that the expression of these HSPs in the nervous system is high. Apart from this finding, investigations have suggested that HSP27 and HSP70 (related to parkin) show a potent protective and anti-apoptotic impact against the damaging outcomes of mutant α-syn toxicity to nerve cells. Therefore, in this study, we aimed to investigate the relationship between these HSPs and apoptosis in patients with PD.

Topics: Aged; alpha-Synuclein; Dopaminergic Neurons; Heat-Shock Proteins; HSP27 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Parkinson Disease; Ubiquitin-Protein Ligases

Parkinson's disease (PD) is a common neurodegenerative condition affecting a significant number of individuals globally, resulting in the presentation of debilitating motor and non-motor symptoms, including bradykinesia, resting tremor, as well as mood and sleep disorders. The pathology of PD has been observed to spread through the central nervous system resulting in progressive brain degeneration and a poor prognosis. Aggregated forms of the protein α-synuclein, particularly intermediary aggregates, referred to as oligomers, or preformed fibrils, have been implicated as the causative agent in the degeneration of neuronal processes, including the dysfunction of axonal transport, mitochondrial activity, and ultimately cellular death. Extracellular vesicles (EVs) have been strongly implicated in the propagation of PD pathology. Current observations suggest that aggregated α-synuclein is transported between neurons via small EVs in a series of exocytosis and endocytosis cellular processes leading to the observed spread of neurotoxicity and cellular death. Despite some understanding of the role of EVs in neurodegeneration, the exact mechanism by which these lipidic particles participate in the progression of Parkinson's pathology is not entirely understood. Here we review the current understanding of the role of EVs in the propagation of PD and explore their potential as a therapeutic target.

Topics: alpha-Synuclein; Extracellular Vesicles; Humans; Neurodegenerative Diseases; Neurons; Parkinson Disease

α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson's disease. Aggregated α-synuclein can impair both synaptic functioning and axonal transport. However, understanding the pathological role that α-synuclein plays at a cellular level is complicated as existing findings are multifaceted and dependent on the mutation, the species, and the quantity of the protein that is involved. This systematic review aims to stratify the research findings to develop a more comprehensive understanding of the role of aggregated α-synuclein on synaptic and axonal proteins in Parkinson's disease models. A literature search of the PubMed, Scopus, and Web of Science databases was conducted and a total of 39 studies were included for analysis. The review provides evidence for the dysregulation or redistribution of synaptic and axonal proteins due to α-synuclein toxicity. However, due to the high quantity of variables that were used in the research investigations, it was challenging to ascertain exactly what effect α-synuclein has on the expression of the proteins. A more standardized experimental approach regarding the variables that are employed in future studies is crucial so that existing literature can be consolidated. New research involving aggregated α-synuclein at the synapse and regarding axonal transport could be advantageous in guiding new treatment solutions.

Topics: alpha-Synuclein; Axons; Humans; Lewy Bodies; Parkinson Disease; Synapses

As a prevalent progressive neurodegenerative disorder, Parkinson's disease (PD) is characterized by the neuropathological hallmark of the loss of nigrostriatal dopaminergic (DAergic) innervation and the appearance of Lewy bodies with aggregated α-synuclein. Although several familial forms of PD have been reported to be associated with several gene variants, most cases in nature are sporadic, triggered by a complex interplay of genetic and environmental risk factors. Numerous epidemiological studies during the past two decades have shown positive associations between PD and several environmental factors, including exposure to neurotoxic pesticides/herbicides and heavy metals as well as traumatic brain injury. Other environmental factors that have been implicated as potential risk factors for PD include industrial chemicals, wood pulp mills, farming, well-water consumption, and rural residence. In this review, we summarize the environmental toxicology of PD with the focus on the elaboration of chemical toxicity and the underlying pathogenic mechanisms associated with exposure to several neurotoxic chemicals, specifically 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, paraquat (PQ), dichloro-diphenyl-trichloroethane (DDT), dieldrin, manganese (Mn), and vanadium (V). Our overview of the current findings from cellular, animal, and human studies of PD provides information for possible intervention strategies aimed at halting the initiation and exacerbation of environmentally linked PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; alpha-Synuclein; Animals; DDT; Dieldrin; Herbicides; Humans; Manganese; Mitochondria; Neuroinflammatory Diseases; Neurotoxicity Syndromes; Oxidative Stress; Paraquat; Parkinson Disease; Pesticides; Risk Factors; Rotenone; Trichloroethanes; Vanadium

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting millions each year. Most PD cases (∼90%) are sporadic, resulting from the age-dependent accumulation of pathogenic effects. One key pathological hallmark of PD progression is the accumulation of alpha-synuclein (α-syn), which has been shown to negatively affect neuronal function and viability. Here, using 3- and 6-month-old Nrf2

Topics: alpha-Synuclein; Animals; Ferroptosis; Humans; Infant; Mice; Neurodegenerative Diseases; NF-E2-Related Factor 2; Parkinson Disease

Parkinson's disease (PD) is the second major progressive neurodegenerative disease, which critically impacts patients' quality of life. Based on genetics, animal models of genetic defects created by gene editing technology have clear advantages in reflecting PD's pathogenesis and pathological characteristics and exploring potential therapeutic targets for PD. In this review, we summarized animal models of genetic defects in various pathogenesis of PD, including α-synuclein abnormal encoding, autophagy-lysosome system defects, ubiquitin protease system defects, and mitochondria-related dysfunction, and discuss their respective advantages, limitations, and application directions to provide a reference for the application of animal models of PD and research on anti-PD therapy.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Neurodegenerative Diseases; Parkinson Disease; Peptide Hydrolases; Quality of Life; Ubiquitin

Injections of pre-formed α-synuclein fibrils (PFFs) or overexpression of α-synuclein using AAV vectors are commonly used as models of Parkinson-like synucleinopathy in rats and mice. In the modified method reviewed here, the "SynFib" model, the PFFs and the AAV vector are administered together unilaterally into the substantia nigra. This approach combines the key features of these two models, i.e., the generation of toxic α-synuclein aggregates and Lewy body-like inclusions, in combination with the increased vulnerability caused by increased cellular levels of α-synuclein. The combined AAV/PFF delivery offers several advantages over the standard PFF model due to the enhanced and accelerated α-synuclein pathology and microglial response induced by the PFF seeds in the presence of an elevated α-synuclein level. Injection of the AAV/PFF mixture into the substantia nigra makes it possible to target a larger proportion of the nigral dopamine neurons and obtain a level of dopamine cell loss (>60%) needed to induce significant impairments in drug-induced and spontaneous motor tests. The SynFib model shares attractive features of the standard 6-OHDA lesion model: a single unilateral stereotaxic intervention; pathology and cell loss developing over a short time span; and the possibility to monitor the degenerative changes using tests of motor behavior.

Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Dopamine; Mice; Parkinson Disease; Rats; Substantia Nigra; Synucleinopathies

Laboratory studies identified changes in the metabolism of halogens in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's disease, which indicates the presence of "accelerated self-halogenation" of CSF and/or an increase in haloperoxidases, specifically serum thyroperoxidase and CSF lactoperoxidase. Furthermore, an excess of some halogenated derivatives, such as advanced oxygenation protein products (AOPP), has been detected in the CSF and serum. "Accelerated self-halogenation" and increased levels of haloperoxidases and AOPP proteins indicate that halogenative stress is present in Parkinson's disease. In addition, 3-iodo-L-tyrosine, a halogenated derivative, shows "parkinsonian" toxicity in experimental models, since it has been observed to induce α-synuclein aggregation and damage to dopaminergic neurons in the mouse brain and intestine. The hypothesis is that patients with Parkinson's disease display halogenative stress related to a haloenzymatic alteration of the synthesis or degradation of oxyacid of halogens and their halogenated derivatives. This halogenative stress would be related to nervous system damage.

Topics: Advanced Oxidation Protein Products; alpha-Synuclein; Animals; Halogens; Humans; Lactoperoxidase; Mice; Parkinson Disease

Parkinson's disease (PD) is the second most common type of neurogenerative disease among middleaged and older people, characterized by aggregation of alpha-synuclein and dopaminergic neuron loss. The microbiota- gut-brain axis is a dynamic bidirectional communication network and is involved in the pathogenesis of PD. The aggregation of misfolded protein alpha-synuclein is a neuropathological characteristic of PD, originates in the gut and migrates to the central nervous system (CNS) through the vagus nerve and olfactory bulb. The change in the architecture of gut microbiota increases the level short-chain fatty acids (SCFAs) and other metabolites, acting on the neuroendocrine system and modulating the concentrations of gamma-Aminobutyric acid (GABA), serotonin, and other neurotransmitters. It also alters the vagus and intestinal signalling, influencing the brain and behaviour by activating microglia and systemic cytokines. Both experimental and clinical reports indicate the role of intestinal dysbiosis and microbiota host interaction in neurodegeneration. Probiotics are live microorganisms that modify the gut microbiota in the small intestine to avoid neurological diseases. Probiotics have been shown in clinical and preclinical studies to be effective in the treatment of PD by balancing the gut microbiota. In this article, we described the role of gut-microbiota in the pathogenesis of PD. The article aims to explore the mechanistic strategy of the gut-brain axis and its relation with motor impairment and the use of probiotics to maintain gut microbial flora and prevent PD-like symptoms.

Topics: Aged; alpha-Synuclein; Brain; Brain-Gut Axis; Gastrointestinal Microbiome; Humans; Parkinson Disease; Probiotics

This article summarizes the underlying biology and current diagnostic and treatment strategies for the cognitive and neuropsychiatric features of Parkinson disease (PD) and dementia with Lewy bodies (DLB).. Cognitive impairment and neuropsychiatric symptoms have been increasingly recognized in PD and DLB, leading to improved diagnosis and treatment strategies. While PD is most associated with and diagnosed by the presence of motor symptoms, nonmotor symptoms can often be the most debilitating for patients. Neuropsychiatric symptoms are highly prevalent nonmotor features and include cognitive impairment, depression, anxiety, psychosis, impulse control disorders, and apathy. Neuropsychiatric symptoms can be difficult to recognize and diagnose in patients with PD, in part because of comorbidity and symptom overlap with core PD features. Treatment strategies are a combination of pharmacologic and nonpharmacologic interventions used in the general population and those specific to PD. DLB is a clinical dementia syndrome, often with similar cognitive, behavioral, autonomic, and motor features as PD. Moreover, DLB has shared underlying pathophysiology with PD, as both are associated with postmortem findings of α-synuclein neuropathology at autopsy and have shared genetic risk and prodromal symptoms. DLB is clinically differentiated from PD by the presenting features of cognitive impairment in DLB, compared with the variable onset of cognitive impairment occurring 1 year or more after established motor onset in PD. Thus, diagnosis and treatment of cognitive impairment and neuropsychiatric symptoms in DLB are similar to that of PD and have important implications for maintaining patient independence and providing support for caregivers because motor, cognitive, and neuropsychiatric symptoms have an additive effect on patient functional disability.. A careful history and physical examination are often needed to accurately diagnose and treat the heterogeneous cognitive and behavioral symptoms of PD and DLB. Accurate diagnosis and treatment of neuropsychiatric symptoms and cognitive impairment in PD and DLB are important, as these are a considerable source of patient disability and caregiver burden.

Topics: alpha-Synuclein; Cognition; Cognitive Dysfunction; Humans; Lewy Body Disease; Parkinson Disease

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder, characterized by the misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies and the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The urge for an early diagnosis biomarker comes from the fact that clinical manifestations of PD are estimated to appear once the substantia nigra has deteriorated and there has been a reduction of the dopamine levels from the striatum. Nowadays, extracellular vesicles (EVs) play an important role in the pathogenesis of neuro-degenerative diseases as PD. A systematic review dated August 2022 was carried out with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses with the aim to analyze the potential role of EVs as biomarkers for PD. From a total of 610 articles retrieved, 29 were eligible. This review discusses the role of EVs biochemistry and their cargo proteins, such as α-syn and DJ-1 among others, detected by a proteomic analysis as well as miRNAs and lncRNAs, as potential biomarkers that can be used to create standardized protocols for early PD diagnosis as well as to evaluate disease severity and progression.

Topics: alpha-Synuclein; Biomarkers; Dopamine; Dopaminergic Neurons; Extracellular Vesicles; Humans; MicroRNAs; Parkinson Disease; Proteomics; RNA, Long Noncoding

Parkinson's disease (PD) is a neurodegenerative disease second only to Alzheimer's disease in terms of prevalence. Previous studies have indicated that the occurrence and progression of PD are associated with mitochondrial dysfunction. Mitochondrial dysfunction is one of the most important causes for apoptosis of dopaminergic neurons. Therefore, maintaining the stability of mitochondrial functioning is a potential strategy in the treatment of PD. Voltage-dependent anion channel (VDAC) is the main component in the outer mitochondrial membrane, and it participates in a variety of biological processes. In this review, we focus on the potential roles of VDACs in the treatment of PD. We found that VDACs are involved in PD by regulating apoptosis, autophagy, and ferroptosis. VDAC1 oligomerization, VDACs ubiquitination, regulation of mitochondrial permeability transition pore (mPTP) by VDACs, and interaction between VDACs and

Topics: alpha-Synuclein; Humans; Mitochondrial Permeability Transition Pore; Neurodegenerative Diseases; Parkinson Disease; Voltage-Dependent Anion Channels

The pathological features of PDD are represented by dopaminergic neuronal death and intracellular

Topics: alpha-Synuclein; Alzheimer Disease; Dementia; Ferroptosis; Humans; Iron; Iron Regulatory Protein 1; Iron Regulatory Protein 2; Neurodegenerative Diseases; Parkinson Disease; Protein Aggregates; Protein Aggregation, Pathological; tau Proteins

Fibrillar aggregates of the α-synuclein (αS) protein are the hallmark of Parkinson's Disease and related neurodegenerative disorders. Characterization of the effects of mutations and post-translational modifications (PTMs) on the αS aggregation rate can provide insight into the mechanism of fibril formation, which remains elusive in spite of intense study. A comprehensive collection (375 examples) of mutant and PTM aggregation rate data measured using the fluorescent probe thioflavin T is presented, as well as a summary of the effects of fluorescent labeling on αS aggregation (20 examples). A curated set of 131 single mutant de novo aggregation experiments are normalized to wild type controls and analyzed in terms of structural data for the monomer and fibrillar forms of αS. These tabulated data serve as a resource to the community to help in interpretation of aggregation experiments and to potentially be used as inputs for computational models of aggregation.

Topics: alpha-Synuclein; Amyloid; Humans; Mutation; Parkinson Disease; Protein Aggregates; Protein Processing, Post-Translational

Recently, there has been growing interest in exosomal biomarkers for their active targeting and specificity for delivering their cargos (proteins, lipids, nucleic acids) from the parent cell to the recipient cell. Currently, the clinical diagnosis of Parkinson's disease (PD) is mainly based on a clinician's neuropsychological examination and motor symptoms (e.g., bradykinesia, rigidity, postural instability, and resting tremor). However, this diagnosis method is not accurate due to overlapping criteria of other neurodegenerative diseases. Exosomes are differentially expressed in PD and a combination of types and contents of exosomes might be used as a biomarker in PD. Here, we systematically reviewed and meta-analyzed exosomal contents, types and sources of exosomes, method of isolation, and protein quantification tools to determine the optimum exosome-related attributes for PD diagnosis. Pubmed, Embase, and ISI Web of Science were searched for relevant studies. 25 studies were included in the meta-analysis. The Ratio of Mean (RoM) with 95% confidence intervals (CI) was calculated to estimate the effect size. Biomarker performances were rated by random-effects meta-analysis with the Restricted Maximum Likelihood (REML) method. The study protocol is available at PROSPERO (CRD42022331885). Exosomal α-synuclein (α-Syn) was significantly altered in PD patients from healthy controls [RoM = 1.67, 95% CI (0.99 to 2.35); p = 0.00] followed by tau [RoM = 1.33, 95% CI (0.79 to 1.87); p = 0.00], PS-129 [RoM = 0.97, 95% CI (0.54 to 1.40); p = 0.00], and DJ-1/PARK7 [RoM = 0.93, 95% CI (0.64 to 1.21); p = 0.00]. Central nervous system derived L1CAM exosome [RoM = 1.24, 95% CI (1.04 to 1.45); p = 0.00] from either plasma [RoM = 1.35, 95% CI (1.09 to 1.61); p = 0.00]; or serum [RoM = 1.47, 95% CI (1.05 to 1.90); p = 0.00] has been found the optimum type of exosome. The exosome isolation by ExoQuick [RoM = 1.16, 95% CI (0.89 to 1.43); p = 0.00] and protein quantification method by ELISA [RoM = 1.28, 95% CI (1.15 to 1.41); p = 0.00] has been found the optimum isolation and quantification method, respectively for PD diagnosis. This meta-analysis suggests that α-Syn in L1CAM exosome derived from blood, isolated by ExoQuick kit, and quantified by ELISA can be used for PD diagnosis.

Topics: alpha-Synuclein; Biomarkers; Central Nervous System; Exosomes; Humans; Neural Cell Adhesion Molecule L1; Parkinson Disease

Improving the quality of life in developed countries has contributed to an increase in its duration, which has led to an increase in the number of reported cases of Alzheimer's disease (AD) and Parkinson's disease (PD) in the world. Today, there are 26.6 million patients with AD in the world and it is suspected that by 2050 the number of such patients may increase four times. Additionally, PD in different countries is recorded among people above 60-65 years old at a level of 167 to 5703 per 100.000 population. The latest studies have made it possible to formulate the main mechanisms of the «microbiota-gut-brain» axis associated with the pathogenesis of some neurodegenerative diseases. In this review, we summarize the currently available information on the possible role of the gut microbiota in the AD and PD development. It was shown that oxidative stress is one of the main pathogenetic mechanisms of the development of neurodegenerative diseases. In addition, the deposition of lipopolysaccharides of gram-negative bacteria and amyloid of microbial origin in the brain tissue of patients with impaired permeability of the intestinal barrier plays an important role in AD. In PD, the synthesis of α-synuclein produced by bacteria and neuroinflammation are of the greatest importance. Knowledge of these mechanisms will allow the development of psychobiotics, which will reduce the risk of neurodegeneration in AD and PD.. Повышение качества жизни в развитых странах способствовало увеличению ее продолжительности, что привело к повышению количества зарегистрированных в мире случаев болезни Альцгеймера (БА) и болезни Паркинсона (БП). Сегодня в мире насчитывается 26,6 млн больных БА, и предполагают, что к 2050 г. число таких пациентов может увеличиться в 4 раза. В свою очередь БП в разных странах регистрируется среди людей старше 60—65 лет на уровне от 167 до 5703 на 100 тыс. населения. Исследования, проведенные в последние годы, позволили сформулировать основные механизмы работы оси «микробиота—кишечник—мозг», которые, как оказалось, могут определять риск развития некоторых нейродегенеративных заболеваний. В настоящем обзоре мы решили обобщить имеющуюся к настоящему моменту информацию о роли микробиоты в патологии нервной системы, сконцентрировав наше внимание на влиянии микробиоты кишечника на риск развития БА и БП. В ходе анализа публикаций показано, что окислительный стресс является одним из ключевых патогенетических механизмов развития нейродегенеративных заболеваний. Кроме того, при БА важную роль играет накопление в мозговой ткани пациентов липополисахаридов грамнегативных бактерий и амилоида микробного происхождения при нарушении проницаемости кишечного барьера. При возникновении же БП наибольшее значение имеют синтез бактериями микробиоты α-синуклеина и нейровоспаление. Знание этих механизмов позволит разработать препараты пробиотиков (так называемых психобиотиков), которые помогут снизить риск нейродегенерации при БА и БП.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Humans; Lipopolysaccharides; Microbiota; Middle Aged; Neurodegenerative Diseases; Parkinson Disease; Quality of Life

The bidirectional communication between the gut and the brain has come up very fascinating in recent years. Many studies have reported that the onset of gastrointestinal issues appears long before the actual manifestation of Parkinson's disease (PD) symptoms. Disturbances in the gut-brain axis have been found to be linked with PD. PD-linked neuropathological changes in the enteric nervous system and significant alteration of gut microbiota suggest a vital role of gut microbiota in PD pathogenesis. Studies have also suggested that aggregation of α-synuclein, one of the major proteins associated with PD neuropathology, might start from the gut and move to the central nervous system (CNS) through the vagus nerve and olfactory bulb. Inflammation in the gut has been suggested to be associated with PD initiation and progression. The flushing out of healthy gut microbiota and replacing with pathogens induces gut inflammation and promotes neuroinflammation in the CNS. Therefore, it is intriguing to understand the mechanism of gut-brain communications associated with the development of PD. This review sheds light on the PD pathology, the gut dysbiosis that is associated with PD and its medications, altered gene expression, pathways and microbial metabolites during PD.

Topics: alpha-Synuclein; Dysbiosis; Gastrointestinal Microbiome; Humans; Inflammation; Parkinson Disease

Autophagy clears protein aggregates, damaged cellular organelles, and pathogens through the lysosome. Although autophagy is highly conserved across all cell types, its activity in each cell is specifically adapted to carry out distinct physiological functions. The role of autophagy in neurons has been well characterized; however, in glial cells, its function remains largely unknown. Microglia are brain-resident macrophages that survey the brain to remove injured neurons, excessive synapses, protein aggregates, and infectious agents. Current studies have demonstrated that dysfunctional microglia contribute to neurodegenerative diseases. In Alzheimer's disease animal models, microglia play a critical role in regulating amyloid plaque formation and neurotoxicity. However, how microglia are involved in Parkinson's disease (PD) remains poorly understood. Propagation of aggregated α-synuclein via cell-to-cell transmission and neuroinflammation have emerged as important mechanisms underlying neuropathologies in PD. Here, we review converging evidence that microglial autophagy maintains α-synuclein homeostasis, regulates neuroinflammation, and confers neuroprotection in PD experimental models.

Topics: alpha-Synuclein; Animals; Autophagy; Homeostasis; Inflammasomes; Microglia; Parkinson Disease; Protein Aggregates

Dopamine metabolism, alpha-synuclein pathology, and iron homeostasis have all been implicated as potential contributors to the unique vulnerability of substantia nigra dopaminergic neurons which preferentially decline in Parkinson's disease and some rare neurodegenerative disorders with shared pathological features. However, the mechanisms contributing to disease progression and resulting in dopaminergic neuron loss in the substantia nigra are still not completely understood. Increasing evidence demonstrates that disrupted dopamine, alpha-synuclein, and/or iron pathways, when combined with the unique morphological, physiological, and metabolic features of this neuron population, may culminate in weakened resilience to multiple stressors. This review analyzes the involvement of each of these pathways in dopamine neuron physiology and function, and discusses how disrupted interplay of dopamine, alpha-synuclein, and iron pathways may synergize to promote pathology and drive the unique vulnerability to disease states. We suggest that elucidating the interactions of dopamine with iron and alpha-synuclein, and the role of dopamine metabolism in driving pathogenic phenotypes will be critical for developing therapeutics to prevent progression in diseases that show degeneration of nigral dopamine neurons such as Parkinson's disease and the rare family of disorders known as Neurodegeneration with Brain Iron Accumulation.

Topics: alpha-Synuclein; Brain; Dopamine; Dopaminergic Neurons; Humans; Iron; Parkinson Disease; Substantia Nigra

Parkinson's disease (PD) is a multisystem alpha-synucleinopathic neurodegenerative disease and the most prevalent neurodegenerative disorder after Alzheimer's disease with a high incidence rate in the elderly population. PD is highly multifactorial in etiology and has complex and wide-ranging pathogenic mechanisms. Environmental exposures and genetic predisposition are prominent risk factors. However, current evidence suggests that an intimate link may exist between the risk factor of sleep disturbance and PD pathogenesis. PD is characterized by the pathological hallmarks of alpha-synuclein aggregations and dopaminergic neuron degeneration in the substantia nigra. The loss of dopamine-producing neurons results in both motor and non-motor symptoms, most commonly, bradykinesia, tremor, rigidity, psychiatric disorders, sleep disorders and gastrointestinal problems. Factors that may exacerbate alpha-synuclein accumulation and dopamine neuron loss include neuroinflammation and glymphatic system impairment. Extracellular alpha-synuclein can induce an inflammatory response which can lead to neural cell death and inhibition of neurogenesis. The glymphatic system functions most optimally to remove extracellular brain solutes during sleep and therefore sleep disruption may be a crucial progression factor as well as a risk factor. This literature review interprets and analyses data from experimental and epidemiological studies to determine the recent advances in establishing a relationship between glymphatic system dysfunction, sleep disturbance, and PD pathogenesis and progression. This review addresses current limitations surrounding the ability to affirm a causal link between improved glymphatic clearance by increased sleep quality in PD prevention and management. Furthermore, this review proposes potential therapeutic approaches that could utilize the protective mechanism of sleep, to promote glymphatic clearance that therefore may reduce disease progression as well as symptom severity in PD patients.

Topics: Aged; alpha-Synuclein; Dopamine; Glymphatic System; Humans; Nerve Degeneration; Neurodegenerative Diseases; Parkinson Disease; Sleep; Sleep Wake Disorders

An increasing number of the population all around the world suffer from age-associated neurodegenerative diseases including Parkinson's disease (PD). This disorder presents different signs of genetic, epigenetic and environmental origin, and molecular, cellular and intracellular dysfunction. At the molecular level, α-synuclein (αSyn) was identified as the principal molecule constituting the Lewy bodies (LB). The gut microbiota participates in the pathogenesis of PD and may contribute to the loss of dopaminergic neurons through mitochondrial dysfunction. The most important pathogenetic link is an imbalance of Ca

Topics: alpha-Synuclein; Dopaminergic Neurons; Humans; Lewy Bodies; Parkinson Disease; Substantia Nigra

α-Synuclein (α-Syn) is a natively unstructured protein, which self-assembles into higher-order aggregates possessing serious pathophysiological implications. α-Syn aberrantly self-assembles into protein aggregates, which have been widely implicated in Parkinson's disease (PD) pathogenesis and other synucleinopathies. The self-assembly of α-Syn involves the structural conversion of soluble monomeric protein into oligomeric intermediates and eventually fibrillar aggregates of amyloids with cross-β-sheet rich conformation. These aggregated α-Syn species majorly constitute the intraneuronal inclusions, which is a hallmark of PD neuropathology. Self-assembly/aggregation of α-Syn is not a single-state conversion process as unfolded protein can access multiple conformational states through the formation of metastable, transient pre-fibrillar intermediate species. Recent studies have indicated that soluble oligomers are the potential neurotoxic species responsible for cell death in PD pathogenesis. The heterogeneous and transient nature of oligomers formed during the early stage of aggregation pathway limit their detailed study in understanding the structure-toxicity relationship. Moreover, the precise molecular events occurring in the early stage of α-Syn aggregation process majorly remain unsolved. Recently, liquid-liquid phase separation (LLPS) of α-Syn has been designated as an alternate nucleation mechanism, which occurs in the early lag phase of the aggregation pathway leading to the formation of dynamic supramolecular assemblies. The stronger self-association among the protein molecules triggers the irreversible liquid-to-solid transition of these supramolecular assemblies into the amyloid-like hydrogel, which may serve as a reservoir entrapping toxic oligomeric intermediates and fibrils. This review strives to provide insights into different modes of α-Syn self-assemblies including LLPS-mediated self-assembly and its recent advancements.

Topics: alpha-Synuclein; Amyloid; Humans; Intrinsically Disordered Proteins; Parkinson Disease; Protein Aggregates

Parkinson's disease (PD) is a progressive neurodegenerative disorder. The classical behavioral defects of PD patients involve motor symptoms such as bradykinesia, tremor, and rigidity, as well as non-motor symptoms such as anosmia, depression, and cognitive impairment. Pathologically, the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the accumulation of α-synuclein (α-syn)-composed Lewy bodies (LBs) and Lewy neurites (LNs) are key hallmarks. Glia are more than mere bystanders that simply support neurons, they actively contribute to almost every aspect of neuronal development and function; glial dysregulation has been implicated in a series of neurodegenerative diseases including PD. Importantly, amounting evidence has added glial activation and neuroinflammation as new features of PD onset and progression. Thus, gaining a better understanding of glia, especially neuron-glia crosstalk, will not only provide insight into brain physiology events but also advance our knowledge of PD pathologies. This review addresses the current understanding of α-syn pathogenesis in PD, with a focus on neuron-glia crosstalk. Particularly, the transmission of α-syn between neurons and glia, α-syn-induced glial activation, and feedbacks of glial activation on DA neuron degeneration are thoroughly discussed. In addition, α-syn aggregation, iron deposition, and glial activation in regulating DA neuron ferroptosis in PD are covered. Lastly, we summarize the preclinical and clinical therapies, especially targeting glia, in PD treatments.

Topics: alpha-Synuclein; Dopaminergic Neurons; Humans; Lewy Bodies; Nerve Degeneration; Parkinson Disease; Substantia Nigra

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It is characterized by the accumulation of α-Synuclein aggregates and the degeneration of dopaminergic neurons in

Topics: alpha-Synuclein; Autophagy; Dopaminergic Neurons; Humans; Parkinson Disease; Substantia Nigra

Parkinson's disease (PD) by its common understanding is a late-onset sporadic movement disorder. However, there is a need to recognize not only the fact that PD pathogenesis expands beyond (or perhaps to) the brain but also that many early-onset patients develop motor signs before the age of 50 years. Indeed, studies have shown that it is likely the protein aggregation observed in the brains of patients with PD precedes the motor symptoms by perhaps a decade. Studies on early-onset forms of PD have shown it to be a heterogeneous disease with multiple genetic and environmental factors determining risk of different forms of disease. Genetic and neuropathological evidence suggests that there are α-synuclein centric forms (e.g., SNCA genomic triplication), and forms that are driven by a breakdown in mitochondrial function and specifically in the process of mitophagy and clearance of damaged mitochondria (e.g., PARKIN and PINK1 recessive loss-of-function mutations). Aligning genetic forms with recognized environmental influences will help better define patients, aid prognosis, and hopefully lead to more accurately targeted clinical trial design. Work is now needed to understand the cross-talk between these two pathomechanisms and determine a sense of independence, it is noted that autopsies studies for both have shown the presence or absence of α-synuclein aggregation. The integration of genetic and environmental data is critical to understand the etiology of early-onset forms of PD and determine how the different pathomechanisms crosstalk.

Topics: alpha-Synuclein; Humans; Middle Aged; Mitochondria; Movement; Mutation; Parkinson Disease; Ubiquitin-Protein Ligases

Parkinson's disease (PD) is a prevalent neurodegenerative disorder that manifests as motor and nonmotor symptoms due to the selective loss of midbrain DArgic (DA) neurons. More and more studies have shown that pathological reactions initiated by autoimmune cells play an essential role in the progression of PD. Autoimmune cells exist in the brain parenchyma, cerebrospinal fluid, and meninges; they are considered inducers of neuroinflammation and regulate the immune in the human brain in PD. For example, T cells can recognize

Topics: alpha-Synuclein; Apoptosis; Dopaminergic Neurons; Humans; Neuroinflammatory Diseases; Neurons; Parkinson Disease

There is no consensus on the efficacy of using α-synuclein as the primary immunotherapy site for Parkinson's disease (PD). The present study sought to investigate the safety and effectiveness of α-synuclein immunotherapy for treating PD.. The databases of CNKI, CBM, Cochrane Library, PubMed, Web of Science, and Embase were searched for randomized controlled trials (RCTs). Cochrane Collaboration's bias assessment tool was used to assess the risk of bias in the included articles, and the included PD patients older than 18 years adopted immunotherapy. Stata 15.0 was employed for statistical analysis.. A total of 6 RCTs were eligible for the present study, involving 606 immunotherapy recipients (using alpha-synuclein immunotherapy) and 254 control individuals (placebo). Our meta-analysis found no statistical difference in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score [weighted mean difference (WMD): -0.72, 95% confidence interval (CI): -1.56 to 0.13, P=0.099], adverse event incidence [relative risk (RR): 1.06, 95% CI: 0.98 to 1.15, P=0.150], headache incidence (RR: 0.95, 95% CI: 0.67 to 1.34, P=0.773), and constipation incidence (RR: 1.47, 95% CI: 0.77 to 2.78, P=0.242). However, the infection rate in the immunotherapy group was higher than in the control group (RR: 2.29, 95% CI: 1.40 to 3.74, P=0.003). The above results indicate that immunotherapy is significantly different from placebo in MDS-UPDRS and adverse event incidence, but it can reduce the incidence of infection rate.. Existing results showed that α-synuclein immunotherapy had no significant effect on PD. high-quality, multi-center, and large-scale clinical studies are desired to corroborate our findings.

Topics: alpha-Synuclein; Humans; Immunotherapy; Parkinson Disease

Parkinson's disease (PD) is characterized by dysfunction of the nigrostriatal system, loss of dopamine neurons and intracellular aggregation of α-synuclein. Recently, both clinical and experimental studies have reported that neuroinflammation and oxidative stress markedly contribute to the etiology of PD. Current clinical pharmacotherapies only temporarily relieve the symptoms of PD, accompanied by many side effects. Hence, searching for natural anti-inflammatory, anti-oxidative and neuroprotective agents has received great attention. Polyunsaturated fatty acids (PUFAs), especially omega (n)-3, are essential lipid nutrients in the human diet and important components of cell membranes. Together by competing with the production of n-6 PUFAs, the precursors of inflammatory mediators, n-3 PUFAs can inhibit microglial activity and neuroinflammation, protect astrocyte function to produce neurotrophins, thereby normalizing neurotransmission and improving neurodegeneration. Thus, with regard to the hypotheses of PD, our and other's recent studies have demonstrated that n-3 PUFAs may improve PD by inhibiting proinflammatory cytokine release, promoting neurotrophic factor expression, recovering mitochondrial function and membrane fluidity, decreasing the levels of oxidant production, maintaining α-synuclein proteostasis, calcium homeostasis, axonal transport, and reducing endoplasmic reticulum stress. This review mainly introduces and analyzes the effect of n-3 PUFA treatments on PD-related behavioral and neuropathological abnormalities in clinical patients and different cellular and animal models of PD. Finally, the limitations and future work in n-3 PUFAs anti-PD area are discussed.

Topics: alpha-Synuclein; Animals; Anti-Inflammatory Agents; Antioxidants; Astrocytes; Fatty Acids, Omega-3; Humans; Microglia; Nerve Growth Factors; Neuroinflammatory Diseases; Neuroprotective Agents; Oxidative Stress; Parkinson Disease

Diabetic retinopathy, the most common complication of diabetes, is a neurodegenerative disease in the eye. And Parkinson's disease, affecting the health of 1-2% of people over 60 years old throughout the world, is the second largest neurodegenerative disease in the brain. As the understanding of diabetic retinopathy and Parkinson's disease deepens, the two diseases are found to show correlation in incidence, similarity in clinical presentation, and close association in pathophysiological mechanisms. To reveal the association between pathophysiological mechanisms of the two disease, in this review, the shared pathophysiological factors of diabetic retinopathy and Parkinson's disease are summarized and classified into dopaminergic system, circadian rhythm, neurotrophic factors, α-synuclein, and Wnt signaling pathways. Furthermore, similar and different mechanisms so far as the shared pathophysiological factors of the two disorders are discussed systematically. Finally, a brief summary and new perspectives are presented to provide new directions for further efforts on the association, exploration, and clinical prevention and treatment of diabetic retinopathy and Parkinson's disease.

Topics: alpha-Synuclein; Brain; Diabetes Mellitus; Diabetic Retinopathy; Dopamine; Humans; Middle Aged; Neurodegenerative Diseases; Parkinson Disease

Dementia with Lewy bodies is the second most common cause of neurodegenerative dementia after Alzheimer's disease. Dementia with Lewy bodies can provide a diagnostic challenge due to the frequent overlap of clinical signs with other neurodegenerative conditions, namely Parkinson's disease dementia, and Alzheimer's disease. Part of this clinical overlap is due to the neuropathological overlap. Dementia with Lewy bodies is characterized by the accumulation of aggregated α-synuclein protein in Lewy bodies, similar to Parkinson's disease and Parkinson's disease dementia. However, it is also frequently accompanied by aggregation of amyloid-beta and tau, the pathological hallmarks of Alzheimer's disease. Neuroimaging is central to the diagnostic process. This review is an overview of both established and evolving imaging methods that can improve diagnostic accuracy and improve management of this disorder.

Topics: alpha-Synuclein; Alzheimer Disease; Dementia; Diagnosis, Differential; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Accumulating evidence suggests that exosomes play a key role in Parkinson's disease (PD). Exosomes may contribute to the PD progression facilitating the spread of pathological alpha-synuclein or activating immune cells. Glial cells also release exosomes, and transmission of exosomes derived from activated glial cells containing inflammatory mediators may contribute to the propagation of the neuroinflammatory response. Glia-to-neuron transmission of exosomes containing alpha-synuclein may contribute to alpha-synuclein propagation and neurodegeneration. Additionally, miRNAs can be transmitted among cells via exosomes inducing changes in the genetic program of the target cell contributing to PD progression. Exosomes also represent a promising drug delivery system. The brain is a difficult target for drugs of all classes because the blood-brain barrier excludes most macromolecular drugs. One of the major challenges is the development of vehicles for robust delivery to the brain. Targeted exosomes may have the potential for delivering therapeutic agents, including proteins and gene therapy molecules, into the brain. This review summarizes recent advances in the role of exosomes in PD pathology progression and their potential use as drug delivery system for PD treatment, the two faces of the exosomes in PD.

Topics: alpha-Synuclein; Brain; Exosomes; Humans; MicroRNAs; Parkinson Disease

Parkinson's disease (PD) is a chronic, progressive and second most prevalent neurological disorder affecting the motor system. Cardinal motor impairment and α-synucleinopathy are the characteristic features of PD. Recently, it has been identified that the gut-brain axis is substantially regulated by the gut microbiome (GM) through an immunological, neuroendocrine, and neural mechanism. However, disturbance in the gut-microbiome-brain axis in PD might proceed to gastrointestinal manifestations intermittently leading to the motor system and the PD pathogenesis itself. The gut microbial toxins may induce the production of α-synuclein (α-syn) aggregates in the enteric nervous system (ENS), which may proliferate and propagate in a prion-like-manner through the vagus nerve to the central nervous system (CNS); supporting the hypothesis that, GM might play a pivotal role in PD pathogenesis. Overstimulated innate immune system due to intestinal bacterial overgrowth or gut dysbiosis and the enhanced intestinal permeability may persuade systemic inflammation, while the activation of enteric glial cells and enteric neurons may contribute to α-synucleinopathy. Gut microbiota can bear a significant impact on neurological outcomes such as learning, memory and cognition. In this review paper, we summarize how the alterations in gut microbiota and ENS inflammation are associated with PD pathogenesis. The evidence supporting the causative role played by gut-associated dysbiosis and microbial byproducts, in the onset of PD is also discussed. We have highlighted the landmark discoveries in the field of PD particularly focusing on the gut-brain axis. A better comprehension of the interaction between the gut-brain axis, gut microbiota, and PD can usher in novel therapeutic and diagnostic approaches.

Topics: alpha-Synuclein; Brain-Gut Axis; Dysbiosis; Enteric Nervous System; Gastrointestinal Microbiome; Humans; Parkinson Disease

Parkinson's disease (PD) is one of the most common neurodegenerative diseases after Alzheimer's disease (AD), afflicting adults above the age of sixty irrespective of gender, race, ethnicity, and social status. PD is characterized by motor dysfunctions, displaying resting tremor, rigidity, bradykinesia, and postural imbalance. Non-motor symptoms, including rapid eye movement (REM) behavior disorder, constipation, and loss of sense of smell, typically occur many years before the appearance of the PD motor symptoms that lead to a diagnosis. The loss of dopaminergic neurons in the substantia nigra, which leads to the motor symptoms seen in PD, is associated with the deposition of aggregated, misfolded α-Synuclein (α-Syn, SNCA) proteins forming Lewy Bodies. Additionally, dysregulation of miRNA (a short form of mRNA) may contribute to the developing pathophysiology in PD and other diseases such as cancer. Overexpression of α-Syn and miRNA in human samples has been found in PD, AD, and dementia. Therefore, evaluating these molecules in urine, present either in the free form or in association with extracellular vesicles of biological fluids, may lead to early biomarkers for clinical diagnosis. Collection of urine is non-invasive and thus beneficial, particularly in geriatric populations, for biomarker analysis. Considering the expression and function of α-Syn and miRNA, we predict that they can be used as early biomarkers in the diagnosis and prognosis of neurodegenerative diseases.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Biomarkers; Humans; MicroRNAs; Parkinson Disease

Parkinson's disease is characterized by nonmotor/motor dysfunction, midbrain dopaminergic neuronal death, and α-synuclein (aSN) deposits. The current hypothesis is that aSN accumulates in the enteric nervous system to reach the brain. However, invertebrate, vertebrate, and nutritional sources of aSN reach the luminal compartment. Submitted to local amyloidogenic forces, the oligomerized proteins' cargo can be sensed and sampled by a specialized mucosal cell to be transmitted to the adjacent enteric nervous system, starting their upward journey to the brain. The present narrative review extends the current mucosal origin of Parkinson's disease, presenting the possibility that the disease starts in the intestinal lumen. If substantiated, eliminating the nutritional sources of aSN (eg, applying a vegetarian diet) might revolutionize the currently used dopaminergic pharmacologic therapy.

Topics: alpha-Synuclein; Brain; Enteric Nervous System; Gastroenterologists; Humans; Parkinson Disease

Parkinson's disease (PD) is a major neurodegenerative disorder which exhibits many of the characteristics of a pandemic. Current therapeutic strategies are centered on the dopaminergic system, with limited efficacy, so that a treatment that has a direct impact on the underlying disease pathogenesis is urgently needed. Although α-synuclein is a privileged target for such therapies, this protein has been in the past wrongly considered as exclusively intracellular, so that the impact of paracrine neurotoxicity mechanisms in PD have been largely ignored. In this article we review the data showing that lipid rafts act as plasma membrane machineries for the formation of α-synuclein pore-like oligomers which trigger an increase of intracellular Ca

Topics: alpha-Synuclein; Disease Progression; Gangliosides; Humans; Membrane Microdomains; Parkinson Disease

Parkinson´s Disease (PD) is the second most common neurodegenerative disorder, affecting ~2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy Bodies (LBs). Recently, Genome-Wide Association Studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.

Topics: Aged; alpha-Synuclein; Dopaminergic Neurons; Genome-Wide Association Study; Humans; Lysosomes; Parkinson Disease

Mitochondrial dysfunction is one of the crucial factors involved in PD's pathogenicity, which emerges from a combination of genetic and environmental factors. These factors cause differential molecular expression in neurons, such as varied transcriptional regulation of genes, elevated oxidative stress, α-synuclein aggregation and endogenous neurotoxins release, which induces epigenetic modifications and triggers energy crisis by damaging mitochondria of the dopaminergic neurons (DN). So far, these events establish a complicated relationship with underlying mechanisms of mitochondrial anomalies in PD, which has remained unclear for years and made PD diagnosis and treatment extremely difficult. Therefore, in this review, we endeavored to discuss the complex association of epigenetic modifications and other associated vital factors in mitochondrial dysfunction. We propose a hypothesis that describes a vicious cycle in which mitochondrial dysfunction and oxidative stress act as a hub for regulating DA neuron's fate in PD. Oxidative stress triggers the release of endogenous neurotoxins (CTIQs) that lead to mitochondrial dysfunction along with abnormal α-synuclein aggregation and epigenetic modifications. These disturbances further intensify oxidative stress and mitochondrial damage, amplifying the synthesis of CTIQs and works vice versa. This vicious cycle may result in the degeneration of DN to hallmark Parkinsonism. Furthermore, we have also highlighted various endogenous compounds and epigenetic marks (neurotoxic and neuroprotective), which may help for devising future diagnostic biomarkers and target specific drugs using novel PD management strategies.

Topics: alpha-Synuclein; Dopaminergic Neurons; Epigenesis, Genetic; Humans; Mitochondria; Neurotoxins; Oxidative Stress; Parkinson Disease

Protein assembly into amyloid fibers underlies many neurodegenerative disorders. In Parkinson's disease, amyloid formation of α-synuclein is linked to brain cell death. The gut-brain axis plays a key role in Parkinson's disease, and initial α-synuclein amyloid formation may occur distant from the brain. Because different amyloidogenic proteins can cross-seed, and α-synuclein is expressed outside the brain, amyloids present in the gut (from food products and secreted by microbiota) may modulate α-synuclein amyloid formation via direct interactions. I here describe existing such data that only began to appear in the literature in the last few years. The striking, but limited, data set-spanning from acceleration to inhibition-calls for additional investigations that may unravel disease mechanisms as well as new treatments.

Topics: alpha-Synuclein; Amyloid; Amyloidogenic Proteins; Gastrointestinal Tract; Humans; Parkinson Disease

Neurogenesis is a key mechanism of brain development and plasticity, which is impaired in chronic neurodegeneration, including Parkinson's disease. The accumulation of aberrant α-synuclein is one of the features of PD. Being secreted, this protein produces a prominent neurotoxic effect, alters synaptic plasticity, deregulates intercellular communication, and supports the development of neuroinflammation, thereby providing propagation of pathological events leading to the establishment of a PD-specific phenotype. Multidirectional and ambiguous effects of α-synuclein on adult neurogenesis suggest that impaired neurogenesis should be considered as a target for the prevention of cell loss and restoration of neurological functions. Thus, stimulation of endogenous neurogenesis or cell-replacement therapy with stem cell-derived differentiated neurons raises new hopes for the development of effective and safe technologies for treating PD neurodegeneration. Given the rapid development of optogenetics, it is not surprising that this method has already been repeatedly tested in manipulating neurogenesis in vivo and in vitro via targeting stem or progenitor cells. However, niche astrocytes could also serve as promising candidates for controlling neuronal differentiation and improving the functional integration of newly formed neurons within the brain tissue. In this review, we mainly focus on current approaches to assess neurogenesis and prospects in the application of optogenetic protocols to restore the neurogenesis in Parkinson's disease.

Topics: alpha-Synuclein; Animals; Astrocytes; Brain; Cell Differentiation; Disease Models, Animal; Hippocampus; Humans; Neural Stem Cells; Neurogenesis; Neuronal Plasticity; Neurons; Optogenetics; Parkinson Disease

Parkinson's disease (PD) and related neurodegenerative disorders, termed the synucleinopathies, are characterized pathologically by the accumulation of protein aggregates containing α-synuclein (aSyn), resulting in progressive neuronal loss. There is considerable need for the development of neuroprotective strategies to halt or slow disease progression in these disorders. To this end, evaluation of genetic mutations associated with the synucleinopathies has helped to elucidate crucial mechanisms of disease pathogenesis, revealing key roles for lysosomal and mitochondrial dysfunction. The GBA1 gene, which encodes the lysosomal hydrolase β-glucocerebrosidase (GCase) is the most common genetic risk factor for PD and is also linked to other neurodegenerative disorders including dementia with Lewy bodies (DLB). Additionally, homozygous mutations in GBA1 are associated with the rare lysosomal storage disorder, Gaucher's disease (GD). In this review, we discuss the current knowledge in the field regarding the diverse roles of GCase in neurons and the multifactorial effects of loss of GCase enzymatic activity. Importantly, GCase has been shown to have a bidirectional relationship with aSyn, resulting in a pathogenic feedback loop that can lead to progressive aSyn accumulation. Alterations in GCase activity have furthermore been linked to multiple distinct pathways involved in neurodegeneration, and therefore GCase has emerged as a promising target for therapeutic drug development for PD and related neurodegenerative disorders, particularly DLB.

Topics: alpha-Synuclein; Gaucher Disease; Glucosylceramidase; Humans; Lysosomes; Neurodegenerative Diseases; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of people worldwide. Two hallmarks of PD are the accumulation of alpha-synuclein and the loss of dopaminergic neurons in the brain. There is no cure for PD, and all existing treatments focus on alleviating the symptoms. PD diagnosis is also based on the symptoms, such as abnormalities of movement, mood, and cognition observed in the patients. Molecular imaging methods such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET) can detect objective alterations in the neurochemical machinery of the brain and help diagnose and study neurodegenerative diseases. This review addresses the application of functional MRI, PET, and SPECT in PD patients. We provide an overview of the imaging targets, discuss the rationale behind target selection, the agents (tracers) with which the imaging can be performed, and the main findings regarding each target's state in PD. Molecular imaging has proven itself effective in supporting clinical diagnosis of PD and has helped reveal that PD is a heterogeneous disorder, which has important implications for the development of future therapies. However, the application of molecular imaging for early diagnosis of PD or for differentiation between PD and atypical parkinsonisms has remained challenging. The final section of the review is dedicated to new imaging targets with which one can detect the PD-related pathological changes upstream from dopaminergic degeneration. The foremost of those targets is alpha-synuclein. We discuss the progress of tracer development achieved so far and challenges on the path toward alpha-synuclein imaging in humans.

Topics: alpha-Synuclein; Humans; Neuroimaging; Parkinson Disease; Positron-Emission Tomography; Tomography, Emission-Computed, Single-Photon

Patients with Parkinson's disease present with signs and symptoms of dysregulation of the peripheral autonomic nervous system that can even precede motor deficits. This dysregulation might reflect early pathology and therefore could be targeted for the development of prodromal or diagnostic biomarkers. Only a few objective clinical tests assess disease progression and are used to evaluate the entire spectrum of autonomic dysregulation in patients with Parkinson's disease. However, results from epidemiological studies and findings from new animal models suggest that the dysfunctional autonomic nervous system is a probable route by which Parkinson's disease pathology can spread both to and from the CNS. The autonomic innervation of the gut, heart, and skin is affected by α-synuclein pathology in the early stages of the disease and might initiate α-synuclein spread via the autonomic connectome to the CNS. The development of easy-to-use and reliable clinical tests of autonomic nervous system function seems crucial for early diagnosis, and for developing strategies to stop or prevent neurodegeneration in Parkinson's disease.

Topics: alpha-Synuclein; Animals; Autonomic Nervous System; Brain; Heart; Humans; Parkinson Disease

The study of platelets in the context of neurodegenerative diseases is intensifying, and increasing evidence suggests that platelets may play an important role in the pathogenesis of neurodegenerative disorders. Therefore, we aim to provide a comprehensive overview of the role of platelets and their diverse activation pathways in the development of these diseases.. Platelets participate in synaptic plasticity, learning, memory, and platelets activated by exercise promote neuronal differentiation in several brain regions. Platelets also contribute to the immune response by modulating their surface protein profile and releasing pro- and anti-inflammatory mediators. In Alzheimer's disease, increased levels of platelet amyloid precursor protein raise the production of amyloid-beta peptides promoting platelet activation, triggering at the same time amyloid-beta fibrillation. In Parkinson's disease, increased platelet α-synuclein is associated with elevated ROS production and mitochondrial dysfunction.. In this review, we revise different platelet activation pathways, those classically involved in hemostasis and wound healing, and alternative activation pathways recently described in the context of neurodegenerative diseases, especially in Alzheimer's disease.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Blood Platelets; Cell Differentiation; Humans; Mitochondria; Neurodegenerative Diseases; Neuronal Plasticity; Parkinson Disease; Platelet Activation; Reactive Oxygen Species

Since the initial identification of alpha-synuclein (α-syn) at the synapse, numerous studies demonstrated that α-syn is a key player in the etiology of Parkinson's disease (PD) and other synucleinopathies. Recent advances underline interactions between α-syn and lipids that also participate in α-syn misfolding and aggregation. In addition, increasing evidence demonstrates that α-syn plays a major role in different steps of synaptic exocytosis. Thus, we reviewed literature showing (1) the interplay among α-syn, lipids, and lipid membranes; (2) advances of α-syn synaptic functions in exocytosis. These data underscore a fundamental role of α-syn/lipid interplay that also contributes to synaptic defects in PD. The importance of lipids in PD is further highlighted by data showing the impact of α-syn on lipid metabolism, modulation of α-syn levels by lipids, as well as the identification of genetic determinants involved in lipid homeostasis associated with α-syn pathologies. While questions still remain, these recent developments open the way to new therapeutic strategies for PD and related disorders including some based on modulating synaptic functions.

Topics: alpha-Synuclein; Animals; Humans; Lipids; Parkinson Disease; Synucleinopathies

Abnormal accumulation of the protein α- synuclein (α-syn) into proteinaceous inclusions called Lewy bodies (LB) is the neuropathological hallmark of Parkinson's disease (PD) and related disorders. Interestingly, a growing body of evidence suggests that LB are also composed of other cellular components such as cellular membrane fragments and vesicular structures, suggesting that dysfunction of the endolysosomal system might also play a role in LB formation and neuronal degeneration. Yet the link between α-syn aggregation and the endolysosomal system disruption is not fully elucidated. In this review, we discuss the potential interaction between α-syn and the endolysosomal system and its impact on PD pathogenesis. We propose that the accumulation of monomeric and aggregated α-syn disrupt vesicles trafficking, docking, and recycling, leading to the impairment of the endolysosomal system, notably the autophagy-lysosomal degradation pathway. Reciprocally, PD-linked mutations in key endosomal/lysosomal machinery genes (LRRK2, GBA, ATP13A2) also contribute to increasing α-syn aggregation and LB formation. Altogether, these observations suggest a potential synergistic role of α-syn and the endolysosomal system in PD pathogenesis and represent a viable target for the development of disease-modifying treatment for PD and related disorders.

Topics: alpha-Synuclein; Animals; Cytoplasmic Vesicles; Endosomes; Humans; Lysosomes; Parkinson Disease; Proteolysis

Multiple system atrophy (MSA) is a rapidly progressive, fatal neurodegenerative disease of uncertain aetiology that belongs to the family of α-synucleinopathies. It clinically presents with parkinsonism, cerebellar, autonomic, and motor impairment in variable combinations. Pathological hallmarks are fibrillary α-synuclein (αSyn)-rich glial cytoplasmic inclusions (GCIs) mainly involving oligodendroglia and to a lesser extent neurons, inducing a multisystem neurodegeneration, glial activation, and widespread demyelinization. The neuronal αSyn pathology of MSA has molecular properties different from Lewy bodies in Parkinson's disease (PD), both of which could serve as a pool of αSyn (prion) seeds that could initiate and drive the pathogenesis of synucleinopathies. The molecular cascade leading to the "prion-like" transfer of "strains" of aggregated αSyn contributing to the progression of the disease is poorly understood, while some presented evidence that MSA is a prion disease. However, this hypothesis is difficult to reconcile with postmortem analysis of human brains and the fact that MSA-like pathology was induced by intracerebral inoculation of human MSA brain homogenates only in homozygous mutant 53T mice, without production of disease-specific GCIs, or with replication of MSA prions in primary astrocyte cultures from transgenic mice expressing human αSyn. Whereas recent intrastriatal injection of Lewy body-derived or synthetic human αSyn fibrils induced PD-like pathology including neuronal αSyn aggregates in macaques, no such transmission of αSyn pathology in non-human primates by MSA brain lysate has been reported until now. Given the similarities between αSyn and prions, there is a considerable debate whether they should be referred to as "prions", "prion-like", "prionoids", or something else. Here, the findings supporting the proposed nature of αSyn as a prion and its self-propagation through seeding as well as the transmissibility of neurodegenerative disorders are discussed. The proof of disease causation rests on the concordance of scientific evidence, none of which has provided convincing evidence for the classification of MSA as a prion disease or its human transmission until now.

Topics: alpha-Synuclein; Animals; Astrocytes; Brain; Humans; Inclusion Bodies; Lewy Bodies; Macaca; Mice; Mice, Transgenic; Models, Theoretical; Multiple System Atrophy; Neurodegenerative Diseases; Neuroglia; Neurons; Parkinson Disease; Parkinsonian Disorders; Prions; Protein Folding

Parkinson's disease (PD) is the second most prevalent late-onset neurodegenerative disorder worldwide after Alzheimer's disease for which available drugs only deliver temporary symptomatic relief. Loss of dopaminergic neurons (DaNs) in the substantia nigra and intracellular alpha-synuclein inclusions are the main hallmarks of the disease but the events that cause this degeneration remain uncertain. Despite cell types other than DaNs such as astrocytes, microglia and oligodendrocytes have been recently associated with the pathogenesis of PD, we still lack an in-depth characterisation of PD-affected brain regions at cell-type resolution that could help our understanding of the disease mechanisms. Nevertheless, publicly available large-scale brain-specific genomic, transcriptomic and epigenomic datasets can be further exploited to extract different layers of cell type-specific biological information for the reconstruction of cell type-specific transcriptional regulatory networks. By intersecting disease risk variants within the networks, it may be possible to study the functional role of these risk variants and their combined effects at cell type- and pathway levels, that, in turn, can facilitate the identification of key regulators involved in disease progression, which are often potential therapeutic targets.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Gene Expression Regulation; Genomics; Humans; Neuroglia; Parkinson Disease; Pars Compacta; Signal Transduction; Transcriptome

Mutations in GBA1, which encode for the protein glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease and dementia with Lewy bodies. In addition, growing evidence now suggests that the loss of GCase activity is also involved in onset of all forms of Parkinson's disease, dementia with Lewy bodies, and other dementias, such as progranulin-linked frontal temporal dementia. As a result, there is significant interest in developing GCase-targeted therapies that have the potential to stop or slow progression of these diseases. Despite this interest in GCase as a therapeutic target, there is significant inconsistency in the methodology for measuring GCase enzymatic activity in disease-modeling systems and patient populations, which could hinder progress in developing GCase therapies. In this review, we discuss the different strategies that have been developed to assess GCase activity and highlight the specific strengths and weaknesses of these approaches as well as the gaps that remain. We also discuss the current and potential role of these different methodologies in preclinical and clinical development of GCase-targeted therapies. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Glucosylceramidase; Humans; Lewy Bodies; Lysosomes; Mutation; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (LBs). Mutations in PD-related genes lead to neuronal pathogenesis through various mechanisms, with known examples including SNCA/α-synuclein (PAKR1), Parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7), and LRRK2 (PARK8). Molecular chaperones/co-chaperones are proteins that aid the folding of other proteins into a functionally active conformation. It has been demonstrated that chaperones/co-chaperones interact with PD-related proteins and regulate their function in PD. HSP70, HSP90 and small heat shock proteins can prevent neurodegeneration by regulating α-syn misfolding, oligomerization and aggregation. The function of chaperones is regulated by co-chaperones such as HSP110, HSP40, HOP, CHIP, and BAG family proteins. Parkin, PINK1 and DJ-1 are PD-related proteins which are associated with mitochondrial function. Molecular chaperones regulate mitochondrial function and protein homeostasis by interacting with these PD-related proteins. This review discusses critical molecular chaperones/co-chaperones and PD-related proteins which contribute to the pathogenesis of PD, hoping to provide new molecular targets for therapeutic interventions to thwart the disease progression instead of only bringing symptomatic relief. Moreover, appreciating the critical role of chaperones in PD can also help us screen efficient biomarkers to identify PD at an early stage.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Dopaminergic Neurons; Humans; Molecular Chaperones; Parkinson Disease; Substantia Nigra; Ubiquitin-Protein Ligases

About 60 years ago, the discovery of a deficiency of dopamine in the nigro-striatal system led to a variety of symptomatic therapeutic strategies to supplement dopamine and to substantially improve the quality of life of patients with Parkinson's disease (PD). Since these seminal developments, neuropathological, neurochemical, molecular biological and genetic discoveries contributed to elucidate the pathology of PD. Oxidative stress, the consequences of reactive oxidative species, reduced antioxidative capacity including loss of glutathione, excitotoxicity, mitochondrial dysfunction, proteasomal dysfunction, apoptosis, lysosomal dysfunction, autophagy, suggested to be causal for ɑ-synuclein fibril formation and aggregation and contributing to neuroinflammation and neural cell death underlying this devastating disorder. However, there are no final conclusions about the triggered pathological mechanism(s) and the follow-up of pathological dysfunctions. Nevertheless, it is a fact, that iron, a major component of oxidative reactions, as well as neuromelanin, the major intraneuronal chelator of iron, undergo an age-dependent increase. And ageing is a major risk factor for PD. Iron is significantly increased in the substantia nigra pars compacta (SNpc) of PD. Reasons for this finding include disturbances in iron-related import and export mechanisms across the blood-brain barrier (BBB), localized opening of the BBB at the nigro-striatal tract including brain vessel pathology. Whether this pathology is of primary or secondary importance is not known. We assume that there is a better fit to the top-down hypotheses and pathogens entering the brain via the olfactory system, then to the bottom-up (gut-brain) hypothesis of PD pathology. Triggers for the bottom-up, the dual-hit and the top-down pathologies include chemicals, viruses and bacteria. If so, hepcidin, a regulator of iron absorption and its distribution into tissues, is suggested to play a major role in the pathogenesis of iron dyshomeostasis and risk for initiating and progressing ɑ-synuclein pathology. The role of glial components to the pathology of PD is still unknown. However, the dramatic loss of glutathione (GSH), which is mainly synthesized in glia, suggests dysfunction of this process, or GSH uptake into neurons. Loss of GSH and increase in SNpc iron concentration have been suggested to be early, may be even pre-symptomatic processes in the pathology of PD, despite the fact that they are progression

Topics: alpha-Synuclein; Humans; Iron; Parkinson Disease; Quality of Life; Substantia Nigra

The neuropeptide substance P (SP) plays an important role in neurodegenerative disorders, among which Parkinson's disease (PD). In the present work we have reviewed the involvement of SP and its preferred receptor (NK1-R) in motor and non-motor PD symptoms, in both PD animal models and patients. Despite PD is primarily a motor disorder, non-motor abnormalities, including olfactory deficits and gastrointestinal dysfunctions, can represent diagnostic PD predictors, according to the hypothesis that the olfactory and the enteric nervous system represent starting points of neurodegeneration, ascending to the brain via the sympathetic fibers and the vagus nerve. In PD patients, the α-synuclein aggregates in the olfactory bulb and the gastrointestinal tract, as well as in the dorsal motor nucleus of the vagus nerve often co-localize with SP, indicating SP-positive neurons as highly vulnerable sites of degeneration. Considering the involvement of the SP/NK1-R in both the periphery and specific brain areas, this system might represent a neuronal substrate for the symptom and disease progression, as well as a therapeutic target for PD.

Topics: alpha-Synuclein; Animals; Brain; Gastrointestinal Tract; Humans; Parkinson Disease; Prognosis; Substance P

Parkinson's disease (PD) is a common neurodegenerative disorder that primarily affects the elderly. While the etiology of PD is likely multifactorial with the involvement of genetic, environmental, aging and other factors, α-synuclein (α-syn) pathology is a pivotal mechanism underlying the development of PD. In recent years, astrocytes have attracted considerable attention in the field. Although astrocytes perform a variety of physiological functions in the brain, they are pivotal mediators of α-syn toxicity since they internalize α-syn released from damaged neurons, and this triggers an inflammatory response, protein degradation dysfunction, mitochondrial dysfunction and endoplasmic reticulum stress. Astrocytes are indispensable coordinators in the background of several genetic mutations, including PARK7, GBA1, LRRK2, ATP13A2, PINK1, PRKN and PLA2G6. As the most abundant glial cells in the brain, functional astrocytes can be replenished and even converted to functional neurons. In this review, we discuss astrocyte dysfunction in PD with an emphasis on α-syn toxicity and genetic modulation and conclude that astrocyte replenishment is a valuable therapeutic approach in PD.

Topics: Aged; alpha-Synuclein; Astrocytes; Humans; Neurodegenerative Diseases; Parkinson Disease; Synucleinopathies

Abnormal accumulation of aggregated α-synuclein (α-Syn) is seen in a variety of neurodegenerative diseases, including Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy body (DLB), Parkinson's disease dementia (PDD), and even subsets of Alzheimer's disease (AD) showing Lewy-body-like pathology. These synucleinopathies exhibit differences in their clinical and pathological representations, reminiscent of prion disorders. Emerging evidence suggests that α-Syn self-assembles and polymerizes into conformationally diverse polymorphs in vitro and in vivo, similar to prions. These α-Syn polymorphs arising from the same precursor protein may exhibit strain-specific biochemical properties and the ability to induce distinct pathological phenotypes upon their inoculation in animal models. In this review, we discuss clinical and pathological variability in synucleinopathies and several aspects of α-Syn fibril polymorphism, including the existence of high-resolution molecular structures and brain-derived strains. The current review sheds light on the recent advances in delineating the structure-pathogenic relationship of α-Syn and how diverse α-Syn molecular polymorphs contribute to the existing clinical heterogeneity in synucleinopathies.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Brain; Humans; Lewy Bodies; Multiple System Atrophy; Parkinson Disease; Prion Diseases; Protein Aggregates

Parkinson's Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery.

Topics: alpha-Synuclein; Biomarkers; Dopaminergic Neurons; Humans; Lewy Bodies; Mitochondria; Neuroinflammatory Diseases; Parkinson Disease; Protein Aggregates; Proteostasis Deficiencies; Reactive Oxygen Species

According to emerging studies, the excessive activation of microglia and the subsequent release of pro-inflammatory cytokines play important roles in the pathogenesis and progression of Parkinson's disease (PD). However, the exact mechanisms governing chronic neuroinflammation remain elusive. Findings demonstrate an elevated level of NLRP3 inflammasome in activated microglia in the substantia nigra of PD patients. Activated NLRP3 inflammasome aggravates the pathology and accelerates the progression of neurodegenerative diseases. Abnormal protein aggregation of α-synuclein (α-syn), a pathologically relevant protein of PD, were reported to activate the NLRP3 inflammasome of microglia through interaction with toll-like receptors (TLRs). This eventually releases pro-inflammatory cytokines through the translocation of nuclear factor kappa-B (NF-κB) and causes an impairment of mitochondria, thus damaging the dopaminergic neurons. Currently, therapeutic drugs for PD are primarily aimed at providing relief from its clinical symptoms, and there are no well-established strategies to halt or reverse this disease. In this review, we aimed to update existing knowledge on the role of the α-syn/TLRs/NF-κB/NLRP3 inflammasome axis and microglial activation in PD. In addition, this review summarizes recent progress on the α-syn/TLRs/NF-κB/NLRP3 inflammasome axis of microglia as a potential target for PD treatment by inhibiting microglial activation.

Topics: alpha-Synuclein; Animals; Biomarkers; Disease Management; Disease Susceptibility; Humans; Inflammasomes; Microglia; Molecular Targeted Therapy; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Parkinson Disease; Protein Aggregation, Pathological; Protein Binding; Signal Transduction; Toll-Like Receptors

The key aspect of the classification of neurodegenerative diseases is the histopathological detection of certain proteins in the brain. The various disease entities are distinguished with respect to the type of detected protein and with respect to the configuration and localization of the corresponding protein aggregates. Aggregates of alpha-synuclein (ASYN) are the defining hallmark of several neurodegenerative disorders termed synucleinopathies. The most well-known diseases in this spectrum are Parkinson's disease (PD) with neuronal detection of Lewy bodies, dementia with Lewy bodies (DLB), with additional detection of beta-amyloid and multiple system atrophy (MSA), where ASYN aggregates are found in glia cells in the form of Papp-Lantos inclusions. ASYN has been identified as a key target for the development of therapeutic approaches to synucleinopathies given its central role in the pathophysiology of these diseases. Current treatment strategies can be roughly classified into six groups: 1) lowering ASYN expression (antisense therapy), 2) inhibition of formation of toxic ASYN aggregates (aggregation inhibitors, chelators), 3) dissolving or removal of intracellular or extracellular toxic AYSN aggregates (active and passive immunotherapy, aggregation inhibitors), 4) enhancement of cellular clearance mechanisms (autophagy, lysosomal microphagy) for removal of toxic forms of alpha-synuclein, 5) modulation of neuroinflammatory processes and 6) neuroprotective strategies. This article summarizes the current therapeutic approaches and sheds light on promising future treatment approaches.. Kernpunkt der Klassifikation neurodegenerativer Erkrankungen ist der histopathologische Nachweis von Ablagerungen bestimmter Proteine im Gehirn. Hierbei unterscheiden sich die verschiedenen Krankheitsentitäten sowohl hinsichtlich der Art der nachweisbaren Proteine als auch hinsichtlich der Konfiguration und Lokalisation der entsprechenden Proteinaggregate. Gemeinsames Kernmerkmal der als Synukleinopathien zusammengefassten Erkrankungen sind Ablagerungen des Proteins α‑Synuklein (ASYN). Die bekanntesten Erkrankungen dieses Spektrums sind die Parkinson-Krankheit (PK) mit neuronalem Nachweis von Lewy-Körperchen, die Demenz vom Lewy-Körper-Typ (DLK) mit zusätzlichem Nachweis von β‑Amyloid-Ablagerungen sowie die seltene Multisystematrophie (MSA) mit glialem Nachweis sog. Papp-Lantos-Körperchen. Da neben der diagnostischen mittlerweile auch die zentrale pathophysiologische Bedeutung des ASYN erwiesen ist, fokussiert sich die Entwicklung neuer Therapien aktuell auf die Beeinflussung der toxischen Wirkung dieses Proteins. Die verschiedenen Therapiekonzepte lassen sich grob in sechs Gruppen zusammenfassen: 1. die Verringerung der ASYN-Expression (Antisense-Therapie), 2. die Verhinderung der Bildung toxischer ASYN-Aggregate (Antiaggregativa, Chelatoren), 3. das Auflösen bzw. die Beseitigung intra- oder extrazellulärer toxischer ASYN-Aggregate (aktive und passive Immuntherapie, Antiaggregativa), 4. die Verstärkung zellulärer Abräummechanismen (Autophagie, lysosomale Mikrophagie) zur Beseitigung toxischer Formen von α‑Synuklein, 5. die Modulation neuroinflammatorischer Prozesse sowie 6. neuroprotektive Strategien. In diesem Artikel fassen wir die aktuellen Therapieentwicklungen zusammen und geben einen Ausblick auf vielversprechende zukünftige Therapieansätze.

Topics: alpha-Synuclein; Humans; Neurodegenerative Diseases; Neurons; Parkinson Disease; Synucleinopathies

Aggregation of alpha-synuclein into inclusion bodies, termed Lewy pathology, is a defining feature of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). In the majority of post mortem cases, the distribution of Lewy pathology seems to follow two overarching patterns: a caudo-rostral pattern with relatively more pathology in the brainstem than in the telencephalon, and an amygdala-centered pattern with the most abundant pathology in the "center of the brain", including the amygdala, entorhinal cortex, and substantia nigra, and relatively less pathology in the lower brainstem and spinal autonomic nuclei. The recent body-first versus brain-first model of Lewy Body Disorders proposes that the initial pathogenic alpha-synuclein in some patients originates in the enteric nervous system with secondary spreading to the brain; and in other patients originates inside the CNS with secondary spreading to the lower brainstem and peripheral autonomic nervous system. Here, we use two existing post mortem datasets to explore the possibility that clinical body-first and brain-first subtypes are equivalent to the caudo-rostral and amygdala-centered patterns of Lewy pathology seen at post mortem.

Topics: alpha-Synuclein; Brain; Brain Stem; Humans; Lewy Body Disease; Parkinson Disease; Substantia Nigra

Parkinson's disease (PD) is characterized by four pathognomonic hallmarks: (1) motor and non-motor deficits; (2) neuroinflammation and oxidative stress; (3) pathological aggregates of the α-synuclein (α-syn) protein; (4) neurodegeneration of the nigrostriatal system. Recent evidence sustains that the aggregation of pathological α-syn occurs in the early stages of the disease, becoming the first trigger of neuroinflammation and subsequent neurodegeneration. Thus, a therapeutic line aims at striking back α-synucleinopathy and neuroinflammation to impede neurodegeneration. Another therapeutic line is restoring the compromised dopaminergic system using neurotrophic factors, particularly the glial cell-derived neurotrophic factor (GDNF). Preclinical studies with GDNF have provided encouraging results but often lack evaluation of anti-α-syn and anti-inflammatory effects. In contrast, clinical trials have yielded imprecise results and have reported the emergence of severe side effects. Here, we analyze the discrepancy between preclinical and clinical outcomes, review the mechanisms of the aggregation of pathological α-syn, including neuroinflammation, and evaluate the neurorestorative properties of GDNF, emphasizing its anti-α-syn and anti-inflammatory effects in preclinical and clinical trials.

Topics: alpha-Synuclein; Animals; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Glial Cell Line-Derived Neurotrophic Factor; Humans; Neuroinflammatory Diseases; Parkinson Disease; Protein Aggregation, Pathological

Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is associated with several disorders, including neurodegenerative diseases, such as Parkinson's disease (PD), and endoplasmic reticulum storage disorders (ERSDs), like alpha-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS). Given the shared pathophysiological mechanisms involved in such conditions, it is necessary to deepen our understanding of the basic principles of misfolding and aggregation akin to these diseases which, although heterogeneous in symptomatology, present similarities that could lead to potential mutual treatments. Here, we review: (i) the pathological bases leading to misfolding and aggregation of proteins involved in PD, AATD, and HHHS: alpha-synuclein, alpha-1-antitrypsin, and fibrinogen, respectively, (ii) the evidence linking each protein aggregation to the stress mechanisms occurring in the endoplasmic reticulum (ER) of each pathology, (iii) a comparison of the mechanisms related to dysfunction of proteostasis and regulation of homeostasis between the diseases (such as the unfolded protein response and/or autophagy), (iv) and clinical perspectives regarding possible common treatments focused on improving the defensive responses to protein aggregation for diseases as different as PD, and ERSDs.

Topics: Afibrinogenemia; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; alpha-Synuclein; Animals; Autophagy; Coagulants; Endoplasmic Reticulum; Fibrinogen; Gene Expression Regulation; Humans; Liver; Neuroprotective Agents; Parkinson Disease; Protease Inhibitors; Protein Aggregates; Protein Folding; Unfolded Protein Response

Parkinson' disease (PD) is a common neurodegenerative disease with the pathological hallmark of alpha-synuclein aggregation within dopaminergic neurons. The etiology of PD comes from a complex interplay between genetic and environmental factors. Though most cases of PD are sporadic; a family history of PD is found in approximately 15% of patients. Pathogenic mutations are found in 5% to 10% of individuals with either familial or sporadic PD. In recent decades, because of the advent of next generation sequencing, more than 25 genes have been identified as causative genes in PD. These findings allow better understanding of the pathogenesis of PD, including aberrant alpha-synuclein homeostasis, defective mitochondrial functions, and impairment of the ubiquitin-proteasome and autophagy-lysosome pathways. Among the PD-causative genes, LRRK2 mutation is the most frequent mutation in autosomal dominant PD and Parkin mutation is prevalent in patients with autosomal recessive or early onset PD. Several genetic epidemiology studies in Asians have revealed a distinctive mutation spectrum from Western populations, reinforcing the importance of ethnic differences in PD. Proper genetic testing is recommended for patients with early onset, a strong family history, or associated red flag clinical features. Considering that clinical trials of disease-modifying therapy targeting patients with specific mutations are ongoing and we are in the era of precision medicine, this review highlights recent updates of genetic findings in patients with PD, focusing on Asian populations and practical recommendations for genetic testing. Keywords: Parkinson's disease, Genetics.

Topics: alpha-Synuclein; Humans; Mutation; Neurodegenerative Diseases; Parkinson Disease

Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of Lewy bodies, Lewy neurites, neuronal cytoplasmic inclusions, and glial cytoplasmic inclusions. Synucleinopathies can be divided into two major disease entities: Lewy body disease and multiple system atrophy (MSA). Common clinical presentations of Lewy body disease are Parkinson's disease (PD), PD with dementia, and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia and MSA with predominant parkinsonism. There are currently no disease-modifying therapies for the synucleinopathies, but information obtained from molecular genetics and models that explore mechanisms of α-synuclein conversion to pathologic oligomers and insoluble fibrils offer hope for eventual therapies. It remains unclear how α-synuclein can be associated with distinct cellular pathologies (e.g., Lewy bodies and glial cytoplasmic inclusions) and what factors determine neuroanatomical and cell type vulnerability. Accumulating evidence from in vitro and in vivo experiments suggests that α-synuclein species derived from Lewy body disease and MSA are distinct "strains" having different seeding properties. Recent advancements in in vitro seeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), not only demonstrate distinct seeding activity in the synucleinopathies, but also offer exciting opportunities for molecular diagnosis using readily accessible peripheral tissue samples. Cryogenic electron microscopy (cryo-EM) structural studies of α-synuclein derived from recombinant or brain-derived filaments provide new insight into mechanisms of seeding in synucleinopathies. In this review, we describe clinical, genetic and neuropathologic features of synucleinopathies, including a discussion of the evolution of classification and staging of Lewy body disease. We also provide a brief discussion on proposed mechanisms of Lewy body formation, as well as evidence supporting the existence of distinct α-synuclein strains in Lewy body disease and MSA.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

Neuronal loss in Parkinson's disease and related brain diseases has been firmly linked to the abundant neuronal protein α-synuclein (αS). However, we have gained surprisingly little insight into how exactly αS exerts toxicity in these diseases. Hypotheses of proteotoxicity, disturbed vesicle trafficking, mitochondrial dysfunction and other toxicity mechanisms have been proposed, and it seems possible that a combination of different mechanisms may drive pathology. A toxicity mechanism that has caught increased attention in the recent years is αS-related lipotoxicity. Lipotoxicity typically occurs in a cell when fatty acids exceed the metabolic needs, triggering a flux into harmful pathways of non-oxidative metabolism. Genetic and experimental approaches have revealed a significant overlap between lipid storage disorders, most notably Gaucher's disease, and synucleinopathies. There is accumulating evidence for lipid aberrations causing synuclein misfolding as well as for αS excess and misfolding causing lipid aberration. Does that mean the key problem in synucleinopathies is lipotoxicity, the accumulation of harmful lipid species or alteration in lipid equilibrium? Here, we review the existing literature in an attempt to get closer to an answer.

Topics: alpha-Synuclein; Gaucher Disease; Humans; Neurons; Parkinson Disease; Synucleinopathies

Parkinson disease (PD) is a progressive neurodegenerative movement disorder characterized by motor and non-motor symptoms due to loss of striatal dopaminergic neurons and disruption of degradation signaling leading to the formation of Lewy bodies (aggregation of α-synuclein). Presently, there are no disease modifying therapy for PD despite improvement in the understanding of the disease pathogenesis. However, the drugs currently used in PD management provide symptomatic relieve for motor symptoms without significant improvement in non-motor complications, thus, a public health burden on caregivers and healthcare systems. There is therefore the need to discover disease modifying therapy with strong potential to halt the disease progression. Recent trend has shown that the dysfunction of lysosomal-autophagy pathway is highly implicated in PD pathology, hence, making autophagy a key player owing to its involvement in degradation and clearance of misfolded α-synuclein (a major hallmark in PD pathology). In this review, we described the current drugs/strategy in the management of PD including targeting the autophagy pathway as a novel approach that could serve as potential intervention for PD management. The discovery of small molecules or natural products capable of enhancing autophagy mechanism could be a promising strategy for PD treatment.

Topics: alpha-Synuclein; Autophagy; Biological Products; Humans; Lysosomes; Parkinson Disease

The critical role of mitochondrial dysfunction in the pathological mechanisms of neurodegenerative disorders, particularly Parkinson's disease (PD), is well established. Compelling evidence indicates that Parkinson's proteins (e.g., α-synuclein, Parkin, PINK1, DJ-1, and LRRK2) are associated with mitochondrial dysfunction and oxidative stress in PD. Significantly, there is a possible central role of alpha-synuclein (α-Syn) in the occurrence of mitochondrial dysfunction and oxidative stress by the mediation of different signaling pathways. Also, tau, traditionally considered as the main component of neurofibrillary tangles, aggregates and amplifies the neurotoxic effects on mitochondria by interacting with α-Syn. Moreover, oxidative stress caused by mitochondrial dysfunction favors assembly of both α-Syn and tau and also plays a key role in the formation of protein aggregates. In this review, we provide an overview of the relationship between these two pathological proteins and mitochondrial dysfunction in PD, and also summarize the underlying mechanisms in the interplay of α-Syn aggregation and phosphorylated tau targeting the mitochondria, to find new strategies to prevent PD processing.

Topics: alpha-Synuclein; Humans; Mitochondria; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease

Multiple system atrophy (MSA) is an adult onset, fatal neurodegenerative disease. However, no reliable biomarker is currently available to guide clinical diagnosis and help to determine the prognosis. Thus, a comprehensive meta-analysis is warranted to determine effective biomarkers for MSA and provide useful guidance for clinical diagnosis.. A comprehensive literature search was made of the PubMed, Embase, Cochrane and Web of Science databases for relevant clinical trial articles for 1984-2019. Two review authors examined the full-text records, respectively, and determined which studies met the inclusion criteria. We estimated the mean difference, standard deviation and 95% confidence intervals.. A total of 28 studies and 11 biomarkers were included in our analysis. Several biomarkers were found to be useful to distinguish MSA patients from healthy controls, including the reduction of phosphorylated tau, α-synuclein (α-syn), 42-amino-acid form of Aβ and total tau (t-tau), the elevation of neurofilament light-chain protein (NFL) in cerebrospinal fluid, the elevation of uric acid and reduction of homocysteine and coenzyme Q10 in plasma. Importantly, α-syn, NFL and t-tau could be used to distinguish MSA from Parkinson's disease (PD), indicating that these three biomarkers could be useful biomarkers in MSA diagnosis.. The findings of our meta-analysis demonstrated diagnostic biomarkers for MSA. Moreover, three biomarkers could be used in differential diagnosis of MSA and PD. The results could be helpful for the early diagnosis of MSA and the accuracy of MSA diagnosis.

Topics: alpha-Synuclein; Biomarkers; Diagnosis, Differential; Humans; Multiple System Atrophy; Parkinson Disease

Parkinson's disease is a progressive and debilitating disorder that has so far eluded attempts to develop disease-modifying treatment. Both epidemiological and genetic studies support a role of neuroinflammation in the pathophysiology of Parkinson's disease. Postmortem studies and experimental analyses suggest the involvement of both innate and adaptive immunity in the degenerative process. There is also some circumstantial evidence for effects of immune therapies on the disease. In the present article, we review 10 unanswered questions related to neuroinflammatory processes in Parkinson's disease with the goal of stimulating research in the field and accelerating the clinical development of neuroprotective therapies based on anti-inflammatory strategies. © 2020 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Humans; Parkinson Disease

Parkinson's Disease (PD) is a common and progressive neurodegenerative disorder characterised by motor impairments as well as non-motor symptoms. While dopamine-based therapies are effective in fighting the symptoms in the early stages of the disease, a lack of neuroprotective drugs means that the disease continues to progress. Along with the traditionally recognised pathological hallmarks of dopaminergic neuronal death and intracellular α-synuclein (α-syn) depositions, iron accumulation, elevated oxidative stress and lipid peroxidation damage are further conspicuous features of PD pathophysiology. However, the underlying mechanisms linking these pathological hallmarks with neurodegeneration still remain unclear. Ferroptosis, a regulated iron dependent cell death pathway involving a lethal accumulation of lipid peroxides, shares several features with PD pathophysiology. Interestingly, α-syn has been functionally linked with the metabolism of both iron and lipid, suggesting a possible interplay between dysregulated α-syn and other PD pathological hallmarks related to ferroptosis. This review will address the importance for understanding these disease mechanisms that could be targeted therapeutically. Anti-ferroptosis molecules are neuroprotective in PD animal models and the anti-ferroptotic iron chelator, deferiprone, slowed disease progression and improved motor function in two independent clinical trials for PD. An ongoing larger multi-centre phase 2 clinical trial will confirm the therapeutic potential of deferiprone and the relevance of ferroptosis in PD. This review addresses the known pathological features of PD in relation to the ferroptosis pathway with therapeutic implications of targeting this cell death pathway.

Topics: alpha-Synuclein; Ferroptosis; Humans; Lipid Peroxidation; Oxidative Stress; Parkinson Disease

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, defined as motor and non-motor symptoms associated with the loss of dopaminergic neurons and a decreased release of dopamine (DA). Currently, PD patients are believed to have a neuropathological basis denoted by the presence of Lewy bodies (LBs) or Lewy neurites (LNs), which mostly comprise α-synuclein (α-syn) inclusions. Remarkably, there is a growing body of evidence indicating that the inclusions undergo template-directed aggregation and propagation via template-directed among the brain and peripheral organs, mainly in a prion-like manner. Interestingly, some studies reported that an integral loop was reminiscent of the mechanism of Parkinson's disease, denoting that α-syn as prionoid was transmitted from the periphery to the brain via specific pathways. Also the systematic life cycle of α-syn in the cellular level is illustrated. In this review, we critically assess landmark evidence in the field of Parkinson's disease with a focus on the genesis and prion-like propagation of the α-syn pathology. The anatomical and cell-to-cell evidences are discussed to depict the theory behind the propagation and transferred pathways. Furthermore, we highlight effective therapeutic perspectives and clinical trials targeting prion-like mechanisms. Major controversies surrounding this topic are also discussed.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Parkinson Disease; Prions

Parkinson's disease (PD) is a complex, age-related, neurodegenerative disease whose pathogenesis remains incompletely understood. Here, we give an overview of the progress that has been made over the past four decades in our understanding of this disorder. We review the role of mitochondria, environmental toxicants, alpha-synuclein and neuroinflammation in the development of PD. We also discuss more recent data from genetics, which strongly support the endosomal-lysosomal pathways and mitophagy as being central to PD. Finally, we discuss the emerging role of the gut-brain axis as a modulator of PD progression. This article is intended to provide a comprehensive, general and practical review of PD pathogenesis for the general neurologist.

Topics: alpha-Synuclein; Brain; Humans; Mitochondria; Neurodegenerative Diseases; Parkinson Disease

Parkinson's disease is one of the most common adult-onset, a chronic disorder involving neurodegeneration, which progressively leads to deprivation of dopaminergic neurons in substantia nigra, causing a subsequent reduction of dopamine levels in the striatum resulting in tremor, myotonia, and dyskinesia. Genetics and environmental factors are believed to be responsible for the onset of Parkinson's disease. The exact pathogenesis of Parkinson's disease is quite complicated and the present anti-Parkinson's disease treatments appear to be clinically insufficient. Comprehensive researches have demonstrated the use of natural products such as ginseng, curcumin, ashwagandha, baicalein, etc. for the symptomatic treatment of this disease. The neuroprotective effects exhibited by these natural products are mainly due to their ability to increase dopamine levels in the striatum, manage oxidative stress, mitochondrial dysfunction, glutathione levels, clear the aggregation of α- synuclein, induce autophagy and decrease the pro-inflammatory cytokines and lipid peroxidation. This paper reviews various natural product studies conducted by scientists to establish the role of natural products (both metabolite extracts as well as pure metabolites) as adjunctive neuroprotective agents.

Topics: alpha-Synuclein; Dopamine; Dopaminergic Neurons; Humans; Neuroprotective Agents; Parkinson Disease; Plant Preparations

Parkinson's disease is a neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons in the substantia nigra. Degenerating neurons contain abnormal aggregates called Lewy bodies, that are predominantly composed of the misfolded and/or mutated alpha-synuclein protein. Post-translational modifications, cellular stress, inflammation and gene mutations are thought to trigger its pathological misfolding and aggregation. With alpha-synuclein pathology being strongly associated with dopaminergic neuronal toxicity, strategies aimed to reduce its burden are expected to be beneficial in slowing disease progression. Moreover, multiple sources of evidence suggest a cell-to-cell transmission of pathological alpha-synuclein in a prion-like manner. Therefore, antibodies targeting extra- or intracellular alpha-synuclein could be efficient in limiting the aggregation and transmission. Several active and passive immunization strategies have been explored to target alpha-synuclein. Here, we summarize immunotherapeutic approaches that were tested in pre-clinical or clinical studies in the last two decades in an attempt to treat Parkinson's disease.

Topics: alpha-Synuclein; Animals; Antibodies, Monoclonal; Humans; Immunization, Passive; Parkinson Disease; Single-Domain Antibodies; Vaccination

A pivotal neuropathological manifestation of synucleinopathies, like Parkinson's disease (PD), is the aggregation of α-synuclein. In a recent cell-to-cell transmission model of α-synuclein, α-synuclein propagation was demonstrated to resemble that of prion proteins in the central nervous system. Furthermore, exosomes, as biomolecule carriers, have been shown to transmit α-synuclein from neuron to neuron. However, the mechanisms underlying exosomal α-synuclein transmission have not been well understood. The NLR family pyrin domain containing 3 protein (NLRP3) inflammasome activation in microglia, and the subsequent release of proinflammatory cytokines, are two crucial pathological events involved in neuroinflammation and PD progression. Research has revealed that the NLRP3 inflammasome may facilitate the secretion of extracellular vesicles, as well as exosomal transmission of proteins like aggregated α-synuclein. However, only a few reports have evaluated these pathogenic mechanisms. Herein we evaluate for the first time the current evidence for the involvement of the NLRP3 inflammasome in microvesicle generation by microglial cells, and the various mechanisms regarding the production, shedding, and content of exosomes in relation to α-synuclein transmission from neuron to neuron. Furthermore, we propose a model of microglial NLRP3 inflammasome-dependent exosome secretion and exosomal α-synuclein transmission in PD. This knowledge may lead to the identification of novel potential targets for drug development and stimulate further research in PD.

Topics: alpha-Synuclein; Animals; Exosomes; Humans; Inflammasomes; Microglia; Neurons; NLR Family, Pyrin Domain-Containing 3 Protein; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra and accumulation of iron and alpha-synuclein; it follows a characteristic pattern throughout the nervous system. Despite decades of successful preclinical neuroprotective studies, no drug has then shown efficacy in clinical trials. Considering this dilemma, we have reviewed and organized solutions of varying importance that can be exclusive or additive, and we outline approaches to help generate successful development of neuroprotective drugs for PD: (1) select patients in which the targeted mechanism is involved in the pathological process associated with the monitoring of target engagement, (2) combine treatments that target multiple pathways, (3) establish earliest interventions and develop better prodromal biomarkers, (4) adopt rigorous methodology and specific disease-relevant designs for disease-modifying clinical trials, (5) customize drug with better brain biodistribution, (6) prioritize repurposed drugs as a first line approach, and (7) adapt preclinical models to the targeted mechanisms with translational biomarkers to increase their predictive value. © 2020 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Humans; Neuroprotection; Neuroprotective Agents; Parkinson Disease; Substantia Nigra; Tissue Distribution

Parkinson's disease (PD) is a progressive neurodegenerative disease where dopaminergic neurons in the substantia nigra are lost, resulting in a decrease in striatal dopamine and, consequently, motor control. Dopaminergic degeneration is associated with the appearance of Lewy bodies, which contain membrane structures and proteins, including α-synuclein (α-Syn), in surviving neurons. PD displays a multifactorial pathology and develops from interactions between multiple elements, such as age, environmental conditions, and genetics. Mutations in the GBA1 gene represent one of the major genetic risk factors for PD. This gene encodes an essential lysosomal enzyme called β-glucocerebrosidase (GCase), which is responsible for degrading the glycolipid glucocerebroside into glucose and ceramide. GCase can generate glucosylated cholesterol via transglucosylation and can also degrade the sterol glucoside. Although the molecular mechanisms that predispose an individual to neurodegeneration remain unknown, the role of cholesterol in PD pathology deserves consideration. Disturbed cellular cholesterol metabolism, as reflected by accumulation of lysosomal cholesterol in GBA1-associated PD cellular models, could contribute to changes in lipid rafts, which are necessary for synaptic localization and vesicle cycling and modulation of synaptic integrity. α-Syn has been implicated in the regulation of neuronal cholesterol, and cholesterol facilitates interactions between α-Syn oligomers. In this review, we integrate the results of previous studies and describe the cholesterol landscape in cellular homeostasis and neuronal function. We discuss its implication in α-Syn and Lewy body pathophysiological mechanisms underlying PD, focusing on the role of GCase and cholesterol. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Cholesterol; Glucosylceramidase; Humans; Lewy Bodies; Neurodegenerative Diseases; Parkinson Disease

Idiopathic Parkinson's disease (iPD) is a movement disorder characterized by the degeneration of dopaminergic neurons and aggregation of the protein α-synuclein. Patients with iPD vary in age of symptom onset, rate of progression, severity of motor and non-motor symptoms, and extent of central and peripheral inflammation. Genetic and environmental factors are believed to act synergistically in iPD pathogenesis. We propose that environmental factors (pesticides and infections) increase the risk for iPD via the immune system and that the role of PD risk genes in immune cells is worthy of investigation. This review highlights the major PD-relevant genes expressed in immune cells and key environmental factors that activate immune cells and, alone or in combination with other factors, may contribute to iPD pathogenesis. By reviewing these interactions, we seek to enable the future development of immunomodulatory approaches to prevent or delay onset of iPD. © 2020 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Dopaminergic Neurons; Humans; Immunity; Inflammation; Parkinson Disease

Mitochondrial dysfunction has been associated with neurodegeneration in Parkinson's disease (PD) for over 30 years. Despite this, the role of mitochondrial dysfunction as an initiator, propagator, or bystander remains undetermined. The discovery of the role of the PD familial genes PTEN-induced putative kinase 1 (PINK1) and parkin (PRKN) in mediating mitochondrial degradation (mitophagy) reaffirmed the importance of this process in PD aetiology. Recently, progress has been made in understanding the upstream and downstream regulators of canonical PINK1/parkin-mediated mitophagy, alongside noncanonical PINK1/parkin mitophagy, in response to mitochondrial damage. Progress has also been made in understanding the role of PD-associated genes, such as SNCA, LRRK2, and CHCHD2, in mitochondrial dysfunction and their overlap with sporadic PD (sPD), opening opportunities for therapeutically targeting mitochondria in PD.

Topics: alpha-Synuclein; DNA-Binding Proteins; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mitochondria; Mitophagy; Parkinson Disease; Protein Kinases; Transcription Factors; Ubiquitin-Protein Ligases

The pathogenesis of Parkinson's disease (PD), which is a progressive neurodegenerative disease, is associated with the formation of protein inclusion bodies called Lewy bodies (LB) or Lewy neurites (LN). α-Synuclein (α-Syn) is a major component of LB and LN. The formation of LB or LN is mediated by formation of α-Syn fibrils, which are formed from α-Syn monomers and oligomers. Additionally, intercellular α-Syn propagation has been proposed to be important for the progression of PD. Thus, various studies have focused on elucidating the role of α-Syn propagation in the pathogenesis of PD. Previous studies have reported that α-Syn species are released from the cells through various pathways, including the unconventional secretion pathways. The released α-Syn species are internalized by the cells through multiple mechanisms, including receptor-mediated endocytosis. Some molecular processes involved in intercellular α-Syn propagation have been recently elucidated. This review discusses the current studies on the molecular mechanisms underlying the release and uptake of α-Syn and their physiological relevance.

Topics: alpha-Synuclein; Animals; Astrocytes; Exosomes; Humans; Lewy Bodies; Microglia; Neurons; Parkinson Disease; Protein Transport

Parkinson's disease (PD) is a complex and widespread neurodegenerative disease characterized by depletion of midbrain dopaminergic (DA) neurons. Key issues are the development of therapies that can stop or reverse the disease progression, identification of dependable biomarkers, and better understanding of the pathophysiological mechanisms of PD. RhoA-ROCK signals appear to have an important role in PD symptoms, making it a possible approach for PD treatment strategies. Activation of RhoA-ROCK (Rho-associated coiled-coil containing protein kinase) appears to stimulate various PD risk factors including aggregation of alpha-synuclein (αSyn), dysregulation of autophagy, and activation of apoptosis. This manuscript reviews current updates about the biology and function of the RhoA-ROCK pathway and discusses the possible role of this signaling pathway in causing the pathogenesis of PD. We conclude that inhibition of the RhoA-ROCK signaling pathway may have high translational potential and could be a promising therapeutic target in PD.

Topics: alpha-Synuclein; Animals; Axons; Humans; Microglia; Parkinson Disease; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction

Parkinson's disease is an increasingly prevalent and currently incurable neurodegenerative disorder. At the molecular level, this disease is characterized by the formation of aberrant intracellular protein deposits known as Lewy bodies. Oligomeric forms of the protein α-synuclein (αS), which are believed to be both intermediates and by-products of Lewy body formation, are considered to be the main pathogenic species. Interactions of such oligomers with lipid membranes are increasingly emerging as a major molecular pathway underpinning their toxicity. Here we review recent progress in our understanding of the interactions of αS oligomers with lipid membranes. We highlight key structural and biophysical features of αS oligomers, the effects of these features on αS oligomer membrane binding properties, and resultant implications for understanding the etiology of Parkinson's disease. We discuss mechanistic modes of αS oligomer-lipid membrane interactions and the effects of environmental factors to such modes. Finally, we provide an overview of the current understanding of the main molecular determinants of αS oligomer toxicity in vivo.

Topics: alpha-Synuclein; Animals; Cell Membrane; Humans; Lewy Bodies; Parkinson Disease; Protein Multimerization

Once recognized as one of the most esoteric diseases of the central nervous system, Parkinson's disease (PD) is now deemed to be a chronic illness contributed by the central, autonomic and enteric nervous systems. Most likely, an accumulation of α-synuclein in the central and enteric nervous systems is the key that supports this viewpoint. Constipation, one of the non-motor hallmarks in roughly two-third of PD patients, is regulated by the composition of gut bacteria, which is assumed to set off the enteric α-synuclein accrual. Vagus nerve is suggested to direct the signal for α-synuclein over-expression and accumulation to the brain. While trillions of microorganisms reside in the intestinal tract, only one third of the proportion inhabits evenly in all individuals. Existence of an impaired gut-microbe-brain axis consonant with dysbiosis could be an epicenter of this inexplicable disorder. Any alteration in the structure and function of the gastrointestinal tract owing to exposure of endogenous or exogenous chemicals or toxicants could lead to dysbiosis. However, inconsistency in the symptoms even after exposure to same chemical or toxicant in PD patients emphatically creates a conundrum. While the level of a few specific neurotransmitters and metabolites is influenced by microbes, implication of dysbiosis is still debatable. Nevertheless, the scientific literature is overflowing with the remarkable observations supporting the role of dysbiosis in PD. Lack of specificity to differentially diagnose PD with non-PD or PD-plus syndrome, to identify highly precise drug targets and to develop therapeutic stratagems to encounter the disease on the basis of this approach, causes us to be open-minded about the dysbiosis theory. The article reviews the facts supporting gut dysbiosis as the foremost trigger for PD onset along with disagreements.

Topics: alpha-Synuclein; Bacteria; Brain; Dysbiosis; Enteric Nervous System; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Parkinson Disease

The cause of most Parkinson's disease cases is unknown. However, it is well documented that mitochondrial dysfunction and misfolded α synuclein aggregation are important cellular abnormalities associated with the disease. In this paper, we use the microcompetition model to show how latent viruses, which infect the central and peripheral nervous systems, can cause the observed mitochondrial dysfunction and excess α synuclein aggregation, and eventually, Parkinson's disease.

Topics: alpha-Synuclein; Animals; Humans; Latent Infection; Mitochondria; Parkinson Disease; Protein Aggregation, Pathological; Virus Latency; Viruses

Amyloid aggregation, which disrupts protein homeostasis, is a common pathological event occurring in human neurodegenerative diseases (NDs). Numerous evidences have shown that the structural diversity, so-called polymorphism, is decisive to the amyloid pathology and is closely associated with the onset, progression, and phenotype of ND. But how could one protein form so many stable structures? Recently, atomic structural evidence has been rapidly mounting to depict the involvement of chemical modifications in the amyloid fibril formation. In this Perspective, we aim to present a hierarchical regulation of chemical modifications including covalent post-translational modifications (PTMs) and noncovalent cofactor binding in governing the polymorphic amyloid formation, based mainly on the latest α-synuclein and Tau fibril structures. We hope to emphasize the determinant role of chemical modifications in amyloid assembly and pathology and to evoke chemical biological approaches to lead the fundamental and therapeutic research on protein amyloid state and the associated NDs.

Topics: Acetylation; alpha-Synuclein; Alzheimer Disease; Amyloid; DNA-Binding Proteins; Humans; Huntington Disease; Models, Molecular; Parkinson Disease; Phosphorylation; Poly Adenosine Diphosphate Ribose; Protein Aggregates; Protein Binding; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Protein Structure, Secondary; tau Proteins

Current therapies for Parkinson's disease (PD) are palliative, of which the levodopa/carbidopa therapy remains the primary choice but is unable to modulate the progression of neurodegeneration. Due to the complication of such a multifactorial disorder and significant limitations of the therapy, numerous genetic approaches have been proved effective in finding out genes and mechanisms implicated in this disease. Following the observation of a higher frequency of PD in Gaucher's disease (GD), a lysosomal storage condition, mutations of glycosylceramidase beta (GBA) encoding glucocerebrosidase (GCase) have been shown to be involved and have been explored in the context of PD. GBA mutations are the most common genetic risk factor of PD. Various studies have revealed the relationships between PD and GBA gene mutations, facilitating a better understanding of this disorder. Various hypotheses delineate that the pathological mutations of GBA minimize the enzymatic activity of GCase, which affects the proliferation and clearance of α-synuclein; this affects the lysosomal homeostasis, exacerbating the endoplasmic reticulum stress or encouraging the mitochondrial dysfunction. Identification of the pathological mechanisms underlying the GBA-associated parkinsonism (GBA + PD) advances our understanding of PD. This review based on current literature aims to elucidate various genetic and clinical characteristics correlated with GBA mutations and to identify the numerous pathological processes underlying GBA + PD. We also delineate the therapeutic strategies to interfere with the mutant GCase function for further improvement of the related α-synuclein-GCase crosstalks. Moreover, the various therapeutic approaches such as gene therapy, chaperone proteins, and histone deacetylase inhibitors for the treatment of GBA + PD are discussed.

Topics: alpha-Synuclein; Gaucher Disease; Genetic Therapy; Glucosylceramidase; Humans; Mutation; Parkinson Disease

Parkinson's disease (PD) is a disabling neurological condition characterized by the loss of dopaminergic neurons. Currently, the treatment for PD is symptomatic and compensates for the endogenous loss of dopamine production. In cases where the pharmacological therapy is only partly beneficial or results in major wearing-off complications, surgical interventions such as deep brain stimulation may be an alternative treatment. The disease cause often remains unknown, but in some patients, a monogenic cause can be identified. Mutations in at least six genes, LRRK2, SNCA, and VPS35 (dominant forms) or Parkin/PRKN, PINK1, and DJ1/PARK7 (recessive forms) have been unequivocally linked to PD pathogenesis. We here systematically screened 8,576 publications on these monogenic PD forms. We identified 2,226 mutation carriers from 456 papers. Levodopa was the most widely applied treatment; only 34 patients were indicated to be untreated at the time of reporting. Notably, detailed treatment data was rarely mentioned including response quantification (good, moderate, minimal) in 951 and/or dose in 293 patients only. Based on available data, levodopa showed an overall good outcome, especially in LRRK2, VPS35, Parkin, and PINK1 mutation carriers ("good" response in 94.6-100%). Side effects of levodopa therapy were reported in ∼15-40%of levodopa-treated patients across genes with dyskinesias as the most frequent one. Non-levodopa medication was indicated to be administered to <200 patients with mainly good outcome. Only a few reports were available on outcomes of brain surgery. Here, most mutation carriers showed a good response. Importantly, none of the available treatments is harmful to one genetic form but effective in another one. In the light of different medication schemes, the progressive nature of PD, and side effects, an improvement of therapeutic options for PD is warranted including a treatabolome database to guide clinicians in treatment decisions. Further, novel disease-cause-modifying drugs are needed.

Topics: alpha-Synuclein; Antiparkinson Agents; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Levodopa; Mutation; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Ubiquitin-Protein Ligases; Vesicular Transport Proteins

For many years, it was postulated that the brain is the organ behind the barrier with an autonomous need for its maintenance. This view has been changed by the concept that the central nervous system is sensitive to the immune processes occurring in the periphery as well as to the infiltration of peripheral immune cells. However, how the immune system might contribute to the development of neurodegenerative diseases, such as Parkinson's disease (PD), remains unclear. PD is a chronic neurodegenerative disorder that affects motor and cognitive functions. Although the precise cause of PD is unknown, studies in both mice and human suggest that alterations in the innate immunity may play a critical role in modulating PD progression. Here, we review recent advancements in our understanding of inflammation and the innate immune mechanisms in PD pathology.

Topics: alpha-Synuclein; Animals; Central Nervous System; Humans; Immunity, Innate; Inflammation; Mice; Microglia; Neuroimmunomodulation; Parkinson Disease

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the progressive deterioration of motor function. Histopathologically, it is widely accepted that the progressive death of selected dopaminergic neuronal populations and the accumulation of hallmark Lewy bodies (LBs) composed of α-synuclein (α-syn) might be the two vital pathogenesis. Extracellular vesicles (EVs) are cell-derived membranous vesicles that are liberated from virtually all cell types including neurons, and harbor a variety of proteins, DNA, mRNA, and lipids. The roles of these vesicles include cell-cell signaling, removal of unwanted proteins, and transfer of pathogens (including misfolded proteins) between cells. In PD, EVs not only enhance the spread of α-syn at distant sites and reduce their clearance but also mediate other PD pathogenesis such as the activation of microglia and the dysfunction of autophagy and lysosomal degradation systems. Recently, clinical evidence for the diagnostic performance of EV-associated biomarkers, particularly exosome biomarkers, has merged. In this regard, we reviewed the recent understanding of the biological roles of EVs as important tools for biomarker discovery and pathological regulators of PD, and discuss the main concerns and challenges for the application of EV biomarkers in the clinical setting.

Topics: alpha-Synuclein; Animals; Biomarkers; Cell Communication; Dopaminergic Neurons; Exosomes; Extracellular Vesicles; Humans; Parkinson Disease

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer,

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyotrophic Lateral Sclerosis; Animals; Diabetes Mellitus, Type 2; Humans; Islet Amyloid Polypeptide; Models, Molecular; Neurodegenerative Diseases; Parkinson Disease; Protein Aggregation, Pathological; Proteostasis Deficiencies; Superoxide Dismutase-1; tau Proteins

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder and is associated with a range of motor and non-motor clinical symptoms. The underlying molecular pathogenesis of PD involves a variety of pathways and mechanisms, including α-synuclein proteostasis, mitochondrial dysfunction, oxidative stress, autophagy and apoptosis, neuroinflammation, and epigenetic regulation. Long non-coding RNAs (lncRNAs) are involved in the regulation of multiple pathological processes of PD. In this review, we provide an overview of large-scale studies on lncRNA expression profiling in PD patients and models, as well as highlight the impacts of lncRNAs on the pathogenesis of PD, which could provide basic information regarding the putative lncRNA-based biomarkers and therapeutic targets for the early diagnosis and treatment strategies for PD.

Topics: alpha-Synuclein; Animals; Apoptosis; Autophagy; Cell Line, Tumor; Epigenesis, Genetic; Gene Expression Profiling; Humans; Mitochondria; Oxidative Stress; Parkinson Disease; RNA, Long Noncoding

Parkin and

Topics: alpha-Synuclein; Female; Humans; Male; Middle Aged; Parkinson Disease; Ubiquitin-Protein Ligases

Parkinson's disease (PD) is a progressive neurodegenerative disease with motor symptoms, such as tremor, akinesia/bradykinesia, rigidity and postural instability due to a loss of nigrostriatal dopaminergic neurons; PD patients also exhibit non-motor symptoms, such as hyposmia, orthostatic hypotension and constipation, which precede motor symptoms. Pathologically, Lewy bodies and neurites, which contains α-synuclein, are observed in the central and peripheral nervous system. To date, it is hypothesized that PD pathology appears first in the olfactory bulb and the enteric nervous system, and propagates progressively through the substantia nigra to finally reach the cerebral cortex. Major medications at present are nosotropic treatments to improve motor dysfunction in PD. Therefore, development of disease-modifying drug is required to slow or prevent PD progression. Astrocytes are known to play an important role in the maintenance of the neuronal environment and exert neuroprotective effects by production of antioxidants and neurotrophic factors and clearing toxic molecules. In the previous study, we demonstrated that astrocytes produced antioxidative molecules metallothionein (MT)-1/2 in response to oxidative stress and protected dopaminergic neurons against oxidative stress. MTs are cysteine-rich proteins possessing antioxidative properties. MTs bind to metals such as zinc (Zn) and copper (Cu) and function in metal homeostasis and detoxification; MTs regulate Zn-mediated transcriptional activation of various genes. Recently, it is reported that MTs prevent Cu-induced aggregation of α-synuclein. In this article, we review a new therapeutic strategy of neuroprotection in PD by targeting MTs in astrocytes.

Topics: alpha-Synuclein; Astrocytes; Carrier Proteins; Humans; Neurodegenerative Diseases; Parkinson Disease

Parkinson's disease (PD), one of the most frequent neurodegenerative disorders, is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN). Genetic vulnerability, aging, environmental insults are believed to contribute to the pathogenesis of PD. However, the cellular and molecular mechanism of dopaminergic neurons degeneration remains incompletely understood. Dopamine (DA) metabolism is a cardinal physiological process in dopaminergic neurons, which is closely related to the loss of dopaminergic neurons in the SN. DA metabolism takes part in several pathological processes of PD neurodegeneration, such as iron metabolism disturbance, α-synuclein mis-folding, endoplasmic reticulum stress, protein degradation dysfunction, neuroinflammatory response, etc. In this review, we will describe altered DA metabolism and its contributions to PD pathogenesis.

Topics: alpha-Synuclein; Dopamine; Dopaminergic Neurons; Humans; Parkinson Disease; Substantia Nigra

The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson's disease (PD) pathogenesis. The stereotypical distribution and evolution of the pathology during disease is often attributed to the cell-to-cell transmission of aSyn between interconnected brain regions. The spreading of conformationally distinct aSyn protein assemblies, commonly referred as strains, is thought to result in a variety of clinically and pathologically heterogenous diseases known as synucleinopathies. Although tremendous progress has been made in the field, the mechanisms involved in the transfer of these assemblies between interconnected neural networks and their role in driving PD progression are still unclear. Here, we present an update of the relevant discoveries supporting or challenging the prion-like spreading hypothesis. We also discuss the importance of aSyn strains in pathology progression and the various putative molecular mechanisms involved in cell-to-cell protein release. Understanding the pathways underlying aSyn propagation will contribute to determining the etiology of PD and related synucleinopathies but also assist in the development of new therapeutic strategies.

Topics: alpha-Synuclein; Brain; Disease Progression; Humans; Parkinson Disease; Prions; Synucleinopathies

A new model of Parkinson's disease (PD) pathogenesis is proposed, the α-Synuclein Origin site and Connectome (SOC) model, incorporating two aspects of α-synuclein pathobiology that impact the disease course for each patient: the anatomical location of the initial α-synuclein inclusion, and α-synuclein propagation dependent on the ipsilateral connections that dominate connectivity of the human brain. In some patients, initial α-synuclein pathology occurs within the CNS, leading to a brain-first subtype of PD. In others, pathology begins in the peripheral autonomic nervous system, leading to a body-first subtype. In brain-first cases, it is proposed that the first pathology appears unilaterally, often in the amygdala. If α-synuclein propagation depends on connection strength, a unilateral focus of pathology will disseminate more to the ipsilateral hemisphere. Thus, α-synuclein spreads mainly to ipsilateral structures including the substantia nigra. The asymmetric distribution of pathology leads to asymmetric dopaminergic degeneration and motor asymmetry. In body-first cases, the α-synuclein pathology ascends via the vagus to both the left and right dorsal motor nuclei of the vagus owing to the overlapping parasympathetic innervation of the gut. Consequently, the initial α-synuclein pathology inside the CNS is more symmetric, which promotes more symmetric propagation in the brainstem, leading to more symmetric dopaminergic degeneration and less motor asymmetry. At diagnosis, body-first patients already have a larger, more symmetric burden of α-synuclein pathology, which in turn promotes faster disease progression and accelerated cognitive decline. The SOC model is supported by a considerable body of existing evidence and may have improved explanatory power.

Topics: alpha-Synuclein; Cognitive Dysfunction; Connectome; Dopamine; Humans; Parkinson Disease; Phenotype; Synucleinopathies

In view of inconsistencies in the association studies of alpha synuclein (SNCA) rs7684318 (chr4: 90655003 T > C) with Parkinson's disease (PD), we conducted a meta-analysis to establish the association of this variant with PD and examined changes in transcription factor binding. SNCA rs7684318 C-allele was identified as genetic risk factor for PD in fixed (OR: 1.53, 95 % CI: 1.40-1.68, p < 0.0001) and random effect (OR: 1.65, 95 % CI: 1.30-2.09, p = 0.0003) models. Heterogeneity was observed in association (Tau

Topics: alpha-Synuclein; Humans; Parkinson Disease; Polymorphism, Single Nucleotide; Protein Binding; Receptors, Notch; Transcription Factors; Wnt Signaling Pathway

Parkinson's disease (PD) is a progressive neurodegenerative disorder resulting from the death of dopamine neurons in the substantia nigra pars compacta. Our understanding of PD biology has been enriched by the identification of genes involved in its rare, inheritable forms, termed PARK genes. These genes encode proteins including α-syn, LRRK2, VPS35, parkin, PINK1, and DJ1, which can cause monogenetic PD when mutated. Investigating the cellular functions of these proteins has been instrumental in identifying signaling pathways that mediate pathology in PD and neuroprotective mechanisms active during homeostatic and pathological conditions. It is now evident that many PD-associated proteins perform multiple functions in PD-associated signaling pathways in neurons. Furthermore, several PARK proteins contribute to non-cell-autonomous mechanisms of neuron death, such as neuroinflammation. A comprehensive understanding of cell-autonomous and non-cell-autonomous pathways involved in PD is essential for developing therapeutics that may slow or halt its progression.

Topics: alpha-Synuclein; Cell Biology; Cell Death; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Neurons; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Signal Transduction; Ubiquitin-Protein Ligases; Vesicular Transport Proteins

Parkinson's disease (PD) is one of the most critical disorders of the elderly and strongly associated with increased disability, and reduced quality of life. PD is a progressive neurodegenerative disease affecting more than six million people worldwide. Evaluation of clinical manifestations, as well as movement disorders by a neurologist and some routine laboratory tests are the most important diagnostic methods for PD. However, routine and old methods have several disadvantages and limitations such as low sensitivity and selectivity, high cost, and need for advanced equipment. Biosensors technology opens up new diagnoses approach for PD with the use of a new platform that allows reliable, repeatable, and multidimensional identification to be made with minimal problem and discomfort for patients. For instance, biosensing systems can provide promising tools for PD treatment and monitoring. Amongst biosensor technology, electrochemical techniques have been at the frontline of this progress, thanks to the developments in material science, such as gold nanoparticles (AuNPs), quantum dots (QDs), and carbon nanotubes (CNTs). This paper evaluates the latest progress in electrochemical and optical biosensors for PD diagnosis.

Topics: Aged; alpha-Synuclein; Biosensing Techniques; Gold; Humans; Metal Nanoparticles; Nanotubes, Carbon; Neurodegenerative Diseases; Parkinson Disease; Quality of Life

α-Synuclein (α-syn), a small highly conserved presynaptic protein containing 140 amino acids, is thought to be the main pathological hallmark in related neurodegenerative disorders. Although the normal function of α-syn is closely involved in the regulation of vesicular neurotransmission in these diseases, the underlying mechanisms of post-translational modifications (PTMs) of α-syn in the pathogenesis of Parkinson's disease (PD) have not been fully characterized. The pathological accumulation of misfolded α-syn has a critical role in PD pathogenesis. Recent studies of factors contributing to α-syn-associated aggregation and misfolding have expanded our understanding of the PD disease process. In this Review, we summarize the structure and physiological function of α-syn, and we further highlight the major PTMs (namely phosphorylation, ubiquitination, nitration, acetylation, truncation, SUMOylation, and O-GlcNAcylation) of α-syn and the effects of these modifications on α-syn aggregation, which may elucidate mechanisms for PD pathogenesis and lay a theoretical foundation for clinical treatment of PD.

Topics: alpha-Synuclein; Humans; Parkinson Disease; Phosphorylation; Protein Processing, Post-Translational; Ubiquitination

A plethora of studies indicate that iron metabolism is dysregulated in Parkinson's disease (PD). The literature reveals well-documented alterations consistent with established dogma, but also intriguing paradoxical observations requiring mechanistic dissection. An important fact is the iron loading in dopaminergic neurons of the substantia nigra pars compacta (SNpc), which are the cells primarily affected in PD. Assessment of these changes reveal increased expression of proteins critical for iron uptake, namely transferrin receptor 1 and the divalent metal transporter 1 (DMT1), and decreased expression of the iron exporter, ferroportin-1 (FPN1). Consistent with this is the activation of iron regulator protein (IRP) RNA-binding activity, which is an important regulator of iron homeostasis, with its activation indicating cytosolic iron deficiency. In fact, IRPs bind to iron-responsive elements (IREs) in the 3ꞌ untranslated region (UTR) of certain mRNAs to stabilize their half-life, while binding to the 5ꞌ UTR prevents translation. Iron loading of dopaminergic neurons in PD may occur through these mechanisms, leading to increased neuronal iron and iron-mediated reactive oxygen species (ROS) generation. The "gold standard" histological marker of PD, Lewy bodies, are mainly composed of α-synuclein, the expression of which is markedly increased in PD. Of note, an atypical IRE exists in the α-synuclein 5ꞌ UTR that may explain its up-regulation by increased iron. This dysregulation could be impacted by the unique autonomous pacemaking of dopaminergic neurons of the SNpc that engages L-type Ca

Topics: alpha-Synuclein; Biology; Humans; Iron; Oxidation-Reduction; Parkinson Disease

Parkinson's disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss of dopaminergic neurons mainly localized in the

Topics: alpha-Synuclein; Animals; DNA-Binding Proteins; DNA, Mitochondrial; Dopaminergic Neurons; Genome-Wide Association Study; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mice; Mitochondria; Neurodegenerative Diseases; Neurons; Organelle Biogenesis; Oxidative Stress; Parkinson Disease; Pars Compacta; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Protein Deglycase DJ-1; Protein Kinases; Transcription Factors; Ubiquitin-Protein Ligases; Vesicular Transport Proteins

The risk of Parkinson's disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson's disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Humans; Inflammation; Parkinson Disease; Risk Factors; Substantia Nigra

Small heat shock proteins (HSPs), such as HSP27, are ubiquitously expressed molecular chaperones and are essential for cellular homeostasis. The major functions of HSP27 include chaperoning misfolded or unfolded polypeptides and protecting cells from toxic stress. Dysregulation of stress proteins is associated with many human diseases including neurodegenerative diseases, such as Parkinson's disease (PD). PD is characterized by the presence of aggregates of α-synuclein in the central and peripheral nervous system, which induces the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and in the autonomic nervous system. Autonomic dysfunction is an important non-motor phenotype of PD, which includes cardiovascular dysregulation, among others. Nowadays, the therapies for PD focus on dopamine (DA) replacement. However, certain non-motor symptoms with a great impact on quality of life do not respond to dopaminergic drugs; therefore, the development and testing of new treatments for non-motor symptoms of PD remain a priority. Since small HSP27 was shown to prevent α-synuclein aggregation and cytotoxicity, this protein might constitute a suitable target to prevent or delay the motor and non-motor symptoms of PD. In the first part of our review, we focus on the cardiovascular dysregulation observed in PD patients. In the second part, we present data on the possible role of HSP27 in preventing the accumulation of amyloid fibrils and aggregated forms of α-synuclein. We also include our own studies, highlighting the possible protective cardiac effects induced by L-DOPA treatment through the enhancement of HSP27 levels and activity.

Topics: alpha-Synuclein; Animals; HSP27 Heat-Shock Proteins; Humans; Parkinson Disease; Protein Aggregates; Protein Binding

Parkinson disease (PD) is a progressive movement functionality disorder resulting in tremor and inability to execute voluntary functions combined with the preponderant non-motor disturbances encompassing constipation and gastrointestinal irritation. Despite continued research, the pathogenesis of PD is not yet clear. The available class of drugs for effective symptomatic management of PD includes a combination of levodopa and carbidopa. In recent past, the link between gut with PD has been explored. According to recent preclinical evidence, pathogens such as virus or bacterium may initiate entry into the gut via the nasal cavity that may aggravate lewy pathology in the gut that eventually propagates and progresses towards the brain via the vagus nerve resulting in the prodromal non-motor symptoms. Additionally, experimental evidence also suggests that alpha-synuclein misfolding commences at a very early stage in the gut and is transported via the vagus nerve prior to seeding PD pathology in the brain. However, this progression and resultant deterioration of the neurones can effectively be altered by an autophagy inducer, Trehalose, although the mechanism behind it is still enigmatic. Hence, this review will mainly focus on analysing the basic components of the gut that might be responsible for aggravating lewy pathology, the mediator(s) responsible for transmission of PD pathology from gut to brain and the important role of trehalose in ameliorating gut dysbiosis related PD complications that would eventually pave the way for therapeutic management of PD.

Topics: alpha-Synuclein; Animals; Autophagy; Brain; Disease Models, Animal; Dysbiosis; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Parkinson Disease; Protein Aggregates; Trehalose

Human brain is composed of 25% of the cholesterol & any dysfunction in brain cholesterol homeostasis contributes to neurodegenerative disorders such as Parkinson, Alzheimer's, Huntington's disease, etc. A growing literature indicates that alteration in neurotransmission & brain cholesterol metabolism takes place in the early stage of the disease. The current paper summarizes the role of cholesterol & its homeostasis in the pathophysiology of Parkinson's disease.. Literature findings suggest the possible role of lipids such as oxysterols, lipoproteins, etc. in Parkinson's disease pathophysiology. Cholesterol performs a diverse role in the brain but any deviation in its levels leads to neurodegeneration. Dysregulation of lipid caused by oxidative stress & inflammation leads to α-synuclein trafficking which contributes to Parkinson's disease progression. Also, α-synuclein by binding to membrane lipid forms lipid-protein complex & results in its aggregation. Different targets such as Phospholipase A2, Stearoyl-CoA desaturase enzyme, proprotein convertase subtilisin/kexin type 9, etc. have been identified as a potential novel approach for Parkinson's disease treatment.. In the current review, we have discussed the possible molecular role of cholesterol homeostasis in Parkinson's disease progression. We also identified potential therapeutic targets that need to be evaluated clinically for the development of Parkinson's treatment.

Topics: alpha-Synuclein; Antiparkinson Agents; Brain; Cholesterol; Drug Discovery; Homeostasis; Humans; Parkinson Disease

Mutations in the gene GBA, encoding glucocerebrosidase (GCase), are the highest genetic risk factor for Parkinson's disease (PD). GCase is a lysosomal glycoprotein responsible for the hydrolysis of glucosylceramide into glucose and ceramide. Mutations in GBA cause a decrease in GCase activity, stability and protein levels which in turn lead to the accumulation of GCase lipid substrates as well as α-synuclein (αS) in vitro and in vivo. αS is the main constituent of Lewy bodies found in the brain of PD patients and an increase in its levels was found to be associated with a decrease in GCase activity/protein levels in vitro and in vivo. In this review, we describe the reported biophysical and biochemical changes that GBA mutations can induce in GCase activity and stability as well as the current overview of the levels of GCase protein/activity, αS and lipids measured in patient-derived samples including post-mortem brains, stem cell-derived neurons, cerebrospinal fluid, blood and fibroblasts as well as in SH-SY5Y cells. In particular, we report how the levels of αS and lipids are affected by/correlated to significant changes in GCase activity/protein levels and which cellular pathways are activated or disrupted by these changes in each model. Finally, we review the current strategies used to revert the changes in the levels of GCase activity/protein, αS and lipids in the context of PD.

Topics: alpha-Synuclein; Glucosylceramidase; Humans; Lipids; Models, Molecular; Parkinson Disease

Parkinson's disease (PD) is a common neurodegenerative disease characterized by a progressive loss of fine motor function that impacts 1-2 out of 1,000 people. PD occurs predominately late in life and lacks a definitive biomarker for early detection. Recent cross-disciplinary progress has implicated the gut as a potential origin of PD pathogenesis. The gut-origin hypothesis has motivated research on gut PD pathology and transmission to the brain, especially during the prodromal stage (10-20 years before motor symptom onset). Early findings have revealed several possible triggers for Lewy pathology - the pathological hallmark of PD - in the gut, suggesting that microbiome and epithelial interactions may play a greater than appreciated role. But the mechanisms driving Lewy pathology and gut-brain transmission in PD remain unknown. Development of artificial α-Synuclein aggregates (α-Syn preformed fibrils) and animal disease models have recapitulated features of PD progression, enabling for the first time, controlled investigation of the gut-origin hypothesis. However, the role of specific cells in PD transmission, such as neurons, remains limited and requires in vitro models for controlled evaluation and perturbation. Human cell populations, three-dimensional organoids, and microfluidics as discovery platforms inch us closer to improving existing treatment for patients by providing platforms for discovery and screening. This review includes a discussion of PD pathology, conventional treatments, in vivo and in vitro models, and future directions. STATEMENT OF SIGNIFICANCE: Parkinson's Disease remains a common neurodegenerative disease with palliative versus causal treatments. Recently, the gut-origin hypothesis, where Parkinson's disease is thought to originate and spread from the gut to the brain, has gained traction as a field of investigation. However, despite the wealth of studies and innovative approaches to accelerate the field, there remains a need for in vitro tools to enable fundamental biological understanding of disease progression, and compound screening and efficacy. In this review, we present a historical perspective of Parkinson's Disease pathogenesis, detection, and conventional therapy, animal and human models investigating the gut-origin hypothesis, in vitro models to enable controlled discovery, and future outlooks for this blossoming field.

Topics: alpha-Synuclein; Animals; Brain; Humans; Neurodegenerative Diseases; Neurons; Parkinson Disease

Alpha-synuclein (α-synuclein) is a protein that is abundantly found in the brain and in a lesser amount in the heart and muscles. The exact role of α-synucleinis is not known, but it is considered to control the movement of synaptic vesicles. Its overexpression in the neurons leads to the formation of Lewy bodies that damage the dopaminergic neurons in the subtantianigra of the midbrain and leads to the progression of Parkinson's Disease (PD). There are evidences showing that aggregates of α-synuclein behave like prions. The present review is an attempt to put forth the nature of α-synuclein as prions.

Topics: alpha-Synuclein; Brain; Dopaminergic Neurons; Humans; Lewy Bodies; Mesencephalon; Parkinson Disease; Prions

Amyloidosis is a concept that implicates disorders and complications that are due to abnormal protein accumulation in different cells and tissues. Protein aggregation-associated diseases are classified according to the type of aggregates and deposition sites, such as neurodegenerative disorders and type 2 diabetes mellitus. Polyphenolic phytochemicals such as curcumin and its derivatives have anti-amyloid effects both in vitro and in animal models; however, the underlying mechanisms are not understood. In this review, we summarized possible mechanisms by which curcumin could interfere with self-assembly processes and reduce amyloid aggregation in amyloidosis. Furthermore, we discuss clinical trials in which curcumin is used as a therapeutic agent for the treatment of diseases linking to protein aggregates.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Clinical Trials as Topic; Creutzfeldt-Jakob Syndrome; Curcumin; Diabetes Mellitus, Type 2; Humans; Huntington Disease; Hypoglycemic Agents; Mitochondria; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Protein Aggregates; tau Proteins

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein aggregates in neurons, nerve fibers or glial cells. Three main types of diseases belong to the synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. All of them develop as a result of an interplay of genetic and environmental factors. Emerging evidence suggests that epigenetic mechanisms play an essential role in the development of synucleinopathies. Since there is no disease-modifying treatment for these disorders at this time, interest is growing in plant-derived chemicals as a potential treatment option. Phytochemicals are substances of plant origin that possess biological activity, which might have effects on human health. Phytochemicals with neuroprotective activity target different elements in pathogenic pathways due to their antioxidants, anti-inflammatory, and antiapoptotic properties, and ability to reduce cellular stress. Multiple recent studies demonstrate that the beneficial effects of phytochemicals may be explained by their ability to modulate the expression of genes implicated in synucleinopathies and other diseases. These substances may regulate transcription directly via transcription factors (TFs) or play the role of epigenetic regulators through their effect on histone modification, DNA methylation, and RNA-based mechanisms. Here, we summarize new data about the impact of phytochemicals on the pathogenesis of synucleinopathies through regulation of gene expression.

Topics: alpha-Synuclein; Brain; Epigenesis, Genetic; Gene Expression; Gene Expression Regulation; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Neuroglia; Neurons; Parkinson Disease; Phytochemicals; Synucleinopathies

The mechanism of nigral dopaminergic neuronal degeneration in Parkinson's disease (PD) is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a narrative review that takes advantage of information related to genes (

Topics: alpha-Synuclein; Animals; Animals, Genetically Modified; Dopaminergic Neurons; Humans; Parkinson Disease; Substantia Nigra

With the world's population ageing, the incidence of Parkinson's disease (PD) is on the rise. In recent years, inflammatory processes have emerged as prominent contributors to the pathology of PD. There is great evidence that microglia have a significant neuroprotective role, and that impaired and over activated microglial phenotypes are present in brains of PD patients. Thereby, PD progression is potentially driven by a vicious cycle between dying neurons and microglia through the instigation of oxidative stress, mitophagy and autophagy dysfunctions, a-synuclein accumulation, and pro-inflammatory cytokine release. Hence, investigating the involvement of microglia is of great importance for future research and treatment of PD. The purpose of this review is to highlight recent findings concerning the microglia-neuronal interplay in PD with a focus on human postmortem immunohistochemistry and single-cell studies, their relation to animal and iPSC-derived models, newly emerging technologies, and the resulting potential of new anti-inflammatory therapies for PD.

Topics: alpha-Synuclein; Animals; Brain; Cytokines; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Humans; Inflammation; Microglia; Nerve Degeneration; Neuroimmunomodulation; Neurons; Neuroprotection; Oxidative Stress; Parkinson Disease

Intracellular vesicular trafficking is essential for neuronal development, function, and homeostasis and serves to process, direct, and sort proteins, lipids, and other cargo throughout the cell. This intricate system of membrane trafficking between different compartments is tightly orchestrated by Ras analog in brain (RAB) GTPases and their effectors. Of the 66 members of the RAB family in humans, many have been implicated in neurodegenerative diseases and impairment of their functions contributes to cellular stress, protein aggregation, and death. Critically, RAB39B loss-of-function mutations are known to be associated with X-linked intellectual disability and with rare early-onset Parkinson's disease. Moreover, recent studies have highlighted altered RAB39B expression in idiopathic cases of several Lewy body diseases (LBDs). This review contextualizes the role of RAB proteins in LBDs and highlights the consequences of RAB39B impairment in terms of endosomal trafficking, neurite outgrowth, synaptic maturation, autophagy, as well as alpha-synuclein homeostasis. Additionally, the potential for therapeutic intervention is examined via a discussion of the recent progress towards the development of specific RAB modulators. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease; rab GTP-Binding Proteins

Topics: alpha-Synuclein; Humans; Immunization; Parkinson Disease; Vaccination

There is a need for objective diagnostic and prognostic biomarkers in Parkinson's disease (PD), partly given the expected increase in clinical trials aimed at demonstrating a disease-modifying effect in early disease. Alpha-synuclein (α-syn) plays a decisive role in the pathogenesis of PD. Here, we review recent publications exploring established and novel methodologies to detect α-syn species in tissues and biofluids.. Using immunohistochemistry (IHC), recent studies have focused on the detection of phosphorylated α-syn (p-α-syn) in cutaneous nerve fibers, reporting varying sensitivity and high specificity for the diagnosis of PD. A predilection for p-α-syn depositions in cutaneous autonomic nerve fibers has emerged, possibly contrasting with other synucleinopathies.Novel studies utilizing the seeding propensity of pathological α-syn have generated encouraging results with regard to diagnostic performance in both tissues and biofluids including skin, submandibular gland, and cerebrospinal fluid.. Detection of neuronal p-α-syn in skin punch biopsies remains a promising minimally invasive diagnostic tool in PD. Seeding assays have emerged as a new method with its diagnostic potential warranting replication in further studies from various tissues and biofluids. Longitudinal studies employing both IHC and seeding assays are needed to identify possible biomarkers of disease progression.

Topics: alpha-Synuclein; Biomarkers; Humans; Neurons; Parkinson Disease; Submandibular Gland

Parkinson's disease (PD) is a neurodegenerative disorder associated with the death of dopaminergic neurons within the substantia nigra of the brain. Melanoma is a cancer of melanocytes, pigmented cells that give rise to skin tone, hair, and eye color. Although these two diseases fundamentally differ, with PD leading to cell degeneration and melanoma leading to cell proliferation, epidemiological evidence has revealed a reciprocal relationship where patients with PD are more susceptible to melanoma and patients with melanoma are more susceptible to PD. The hallmark pathology observed in PD brains is intracellular inclusions, of which the primary component is proteinaceous α-synuclein (α-syn) amyloid fibrils. α-Syn also has been detected in cultured melanoma cells and tissues derived from patients with melanoma, where an inverse correlation exists between α-syn expression and pigmentation. Although this has led to the prevailing hypothesis that α-syn inhibits enzymes involved in melanin biosynthesis, we recently reported an alternative hypothesis in which α-syn interacts with and modulates the aggregation of Pmel17, a functional amyloid that serves as a scaffold for melanin biosynthesis. In this perspective, we review the literature describing the epidemiological and molecular connections between PD and melanoma, presenting both the prevailing hypothesis and our amyloid-centric hypothesis. We offer our views of the essential questions that remain unanswered to motivate future investigations. Understanding the behavior of α-syn in melanoma could not only provide novel approaches for treating melanoma but also could reveal insights into the role of α-syn in PD. © 2021 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Amyloid; Humans; Melanoma; Parkinson Disease; Substantia Nigra

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of human COVID-19, not only causes flu-like symptoms and gut microbiome complications but a large number of infected individuals also experience a host of neurological symptoms including loss of smell and taste, seizures, difficulty concentrating, decreased alertness, and brain inflammation. Although SARS-CoV-2 infections are not more prevalent in Parkinson's disease patients, a higher mortality rate has been reported not only associated with older age and longer disease duration, but also through several mechanisms, such as interactions with the brain dopaminergic system and through systemic inflammatory responses. Indeed, a number of the neurological symptoms seen in COVID-19 patients, as well as the alterations in the gut microbiome, are also prevalent in patients with Parkinson's disease. Furthermore, biochemical pathways such as oxidative stress, inflammation, and protein aggregation have shared commonalities between Parkinson's disease and COVID-19 disease progression. In this review, we describe and compare the numerous similarities and intersections between neurodegeneration in Parkinson's disease and RNA viral infections, emphasizing the current SARS-CoV-2 global health crisis.

Topics: Aged; alpha-Synuclein; Cognition Disorders; COVID-19; Cytokines; Diet; Disease Progression; Dysbiosis; Gastrointestinal Microbiome; Humans; Inflammation; Metals, Heavy; Models, Neurological; Nerve Degeneration; Olfactory Bulb; Oxidative Stress; Parkinson Disease; Practice Guidelines as Topic; Protein Aggregation, Pathological; Reactive Oxygen Species; RNA Virus Infections; SARS-CoV-2; Sensation Disorders

A pathological hallmark of the neurodegenerative disorder, Parkinson's disease (PD), is aggregation of toxic forms of the presynaptic protein, α-synuclein in structures known as Lewy bodies. α-Synuclein pathology is found in both the brain and gastrointestinal tracts of affected individuals, possibly due to the movement of this protein along the vagus nerve that connects the brain to the gut. In this review, we discuss current insights into the spread of α-synuclein pathology along the gut-brain axis, which could be targeted for therapeutic interventions. The prion-like propagation of α-synuclein, and the clinical manifestations of gastrointestinal dysfunction in individuals living with PD, are discussed. There is currently insufficient evidence that surgical alteration of the vagus nerve, or removal of gut-associated lymphoid tissues, such as the appendix and tonsils, are protective against PD. Furthermore, we propose curcumin as a potential candidate to prevent the spread of α-synuclein pathology in the body by curcumin binding to α-synuclein's non-amyloid β-component (NAC) domain. Curcumin is an active component of the food spice turmeric and is known for its antioxidant, anti-inflammatory, and potentially neuroprotective properties. We hypothesize that once α-synuclein is bound to curcumin, both molecules are subsequently excreted from the body. Therefore, dietary supplementation with curcumin over one's lifetime has potential as a novel approach to complement existing PD treatment and/or prevention strategies. Future studies are required to validate this hypothesis, but if successful, this could represent a significant step towards improved nutrient-based therapeutic interventions and preventative strategies for this debilitating and currently incurable disorder.

Topics: alpha-Synuclein; Brain; Curcumin; Humans; Parkinson Disease; Prions

In Parkinson's disease, aggregates of α-synuclein within Lewy bodies and Lewy neurites represent neuropathological hallmarks. However, the cellular and molecular mechanisms triggering oligomeric and fibrillary α-synuclein aggregation are not fully understood. Recent evidence indicates that oxidative stress induced by metal ions and post-translational modifications such as phosphorylation, ubiquitination, nitration, glycation, and SUMOylation affect α-synuclein conformation along with its aggregation propensity and neurotoxic profiles. In addition, proteolytic cleavage of α-synuclein by specific proteases results in the formation of a broad spectrum of fragments with consecutively altered and not fully understood physiological and/or pathological properties. In the present review, we summarize the current knowledge on proteolytical α-synuclein cleavage by neurosin, calpain-1, cathepsin D, and matrix metalloproteinase-3 in health and disease. We also shed light on the contribution of the same enzymes to proteolytical processing of pathogenic proteins in Alzheimer's disease and report potential cross-disease mechanisms of pathogenic protein aggregation.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Humans; Parkinson Disease; Peptide Hydrolases; Protein Aggregates; Proteolysis

Although it is not yet universally accepted that all neurodegenerative diseases (NDs) are prion disorders, there is little disagreement that Alzheimer's disease (AD), Parkinson's disease, frontotemporal dementia (FTD), and other NDs are a consequence of protein misfolding, aggregation, and spread. This widely accepted perspective arose from the prion hypothesis, which resulted from investigations on scrapie, a common transmissible disease of sheep and goats. The prion hypothesis argued that the causative infectious agent of scrapie was a novel proteinaceous pathogen devoid of functional nucleic acids and distinct from viruses, viroids, and bacteria. At the time, it seemed impossible that an infectious agent like the one causing scrapie could replicate and exist as diverse microbiological strains without nucleic acids. However, aggregates of a misfolded host-encoded protein, designated the prion protein (PrP), were shown to be the cause of scrapie as well as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome (GSS), which are similar NDs in humans. This review discusses historical research on diseases caused by PrP misfolding, emphasizing principles of pathogenesis that were later found to be core features of other NDs. For example, the discovery that familial prion diseases can be caused by mutations in PrP was important for understanding prion replication and disease susceptibility not only for rare PrP diseases but also for far more common NDs involving other proteins. We compare diseases caused by misfolding and aggregation of APP-derived Aβ peptides, tau, and α-synuclein with PrP prion disorders and argue for the classification of NDs caused by misfolding of these proteins as prion diseases. Deciphering the molecular pathogenesis of NDs as prion-mediated has provided new approaches for finding therapies for these intractable, invariably fatal disorders and has revolutionized the field.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Creutzfeldt-Jakob Syndrome; Frontotemporal Dementia; Gene Expression; Gerstmann-Straussler-Scheinker Disease; Humans; Mice; Mutation; Parkinson Disease; Prion Proteins; Prions; Protein Folding; Scrapie; Sheep; tau Proteins

Alpha-Synuclein (αSyn) is a protein whose function is still debated, as well as its role in modulation of mitochondrial function in both physiological and pathological conditions. Mitochondrial porins or Voltage-Dependent Anion Channel (VDAC) proteins are the main gates for ADP/ATP and various substrates towards the organelle. Furthermore, they act as a mitochondrial hub for many cytosolic proteins, including αSyn. This review analyzes the main aspects of αSyn-mitochondria interaction, focusing on the role of VDAC and its emerging involvement in the pathological processes.

Topics: alpha-Synuclein; Animals; Cytosol; Humans; Mitochondria; Nerve Degeneration; Parkinson Disease; Voltage-Dependent Anion Channels

The potential to treat neurodegenerative diseases (NDs) of the major bioactive compound of green tea, epigallocatechin-3-gallate (EGCG), is well documented. Numerous findings now suggest that EGCG targets protein misfolding and aggregation, a common cause and pathological mechanism in many NDs. Several studies have shown that EGCG interacts with misfolded proteins such as amyloid beta-peptide (Aβ), linked to Alzheimer's disease (AD), and α-synuclein, linked to Parkinson's disease (PD). To date, NDs constitute a serious public health problem, causing a financial burden for health care systems worldwide. Although current treatments provide symptomatic relief, they do not stop or even slow the progression of these devastating disorders. Therefore, there is an urgent need to develop effective drugs for these incurable ailments. It is expected that targeting protein misfolding can serve as a therapeutic strategy for many NDs since protein misfolding is a common cause of neurodegeneration. In this context, EGCG may offer great potential opportunities in drug discovery for NDs. Therefore, this review critically discusses the role of EGCG in NDs drug discovery and provides updated information on the scientific evidence that EGCG can potentially be used to treat many of these fatal brain disorders.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Catechin; Drug Discovery; Humans; Molecular Targeted Therapy; Neurodegenerative Diseases; Parkinson Disease; Protein Aggregates; Protein Folding; Tea

Biomarkers for neurodegenerative diseases are needed to improve the diagnostic workup in the clinic but also to facilitate the development and monitoring of effective disease-modifying therapies. Positron emission tomography methods detecting amyloid-β and tau pathology in Alzheimer's disease have been increasingly used to improve the design of clinical trials and observational studies. In recent years, easily accessible and cost-effective blood-based biomarkers detecting the same Alzheimer's disease pathologies have been developed, which might revolutionize the diagnostic workup of Alzheimer's disease globally. Relevant biomarkers for α-synuclein pathology in Parkinson's disease are also emerging, as well as blood-based markers of general neurodegeneration and glial activation. This review presents an overview of the latest advances in the field of biomarkers for neurodegenerative diseases. Future directions are discussed regarding implementation of novel biomarkers in clinical practice and trials.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Humans; Neurodegenerative Diseases; Parkinson Disease; Positron-Emission Tomography; tau Proteins

The protein alpha-Synuclein (α-Syn) is a key contributor to the etiology of Parkinson's disease (PD) with aggregation, trans-neuronal spread, and/or depletion of α-Syn being viewed as crucial events in the molecular processes that result in neurodegeneration. The exact succession of pathological occurrences that lead to neuronal death are still largely unknown and are likely to be multifactorial in nature. Despite this unknown, α-Syn dose and stability, autophagy-lysosomal dysfunction, and inflammation, amongst other cellular impairments, have all been described as participatory events in the neurodegenerative process. To that end, in this review we discuss the logical points for gene therapy to intervene in α-Syn-mediated disease and review the preclinical body of work where gene therapy has been used, or could conceptually be used, to ameliorate α-Syn induced neurotoxicity. We discuss gene therapy in the traditional sense of modulating gene expression, as well as the use of viral vectors and nanoparticles as methods to deliver other therapeutic modalities.

Topics: alpha-Synuclein; Genetic Therapy; Humans; Lysosomes; Parkinson Disease; Synucleinopathies

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and abnormal aggregates of α-synuclein protein called Lewy bodies. To date, there is no drug that can definitely slow down or stop the progression of this disease. The discovery of the cell-to-cell transmission of pathologic α-synuclein seeds offers the possibility to explore novel treatment strategies to prevent the spread of α-synuclein, with the purpose of slowing down the progression of PD in its tracks. Although recent studies have made tremendous progress in understanding how α-synuclein spreads throughout the brain, neuroinflammation seems to play a crucial role in the development of α-synuclein pathology in PD. The activation of microglia, one of the hallmarks of the neuroinflammatory process, is suggested to influence the neuron-to-neuron transmission of α-synuclein. This review summarizes how activated microglia facilitate this process, and focuses on the following mechanisms including the activation of microglia in PD, the reduced ability of activated microglia to clear α-synuclein and increased migratory capacity of microglia in PD, as well as the cooperation between microglia and exosomes in mediating α-synuclein release and propagation. In conclusion, this article help collate information on microglia in-relation to PD.

Topics: alpha-Synuclein; Animals; Brain; Dopaminergic Neurons; Humans; Macrophages; Microglia; Parkinson Disease

Seventy years ago, we learned from Chris Anfinsen that the stereochemical code necessary to fold a protein is embedded into its amino acid sequence. In water, protein morphogenesis is a spontaneous reversible process leading from an ensemble of disordered structures to the ordered functionally competent protein; conforming to Aristotle's definition of substance, the synolon of matter and form. The overall process of folding is generally consistent with a two state transition between the native and the denatured protein: not only the denatured state is an ensemble of several structures, but also the native protein populates distinct functionally relevant conformational (sub)states. This two-state view should be revised, given that any globular protein can populate a peculiar third state called amyloid, characterized by an overall architecture that at variance with the native state, is by-and-large independent of the primary structure. In a nut shell, we should accept that beside the folded and unfolded states, any protein can populate a third state called amyloid which gained center stage being the hallmark of incurable neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases as well as others. These fatal diseases are characterized by clear-cut clinical differences, yet display some commonalities such as the presence in the brain of amyloid deposits constituted by one misfolded protein specific for each disease. Some aspects of this complex problem are summarized here as an excursus from the prion's fibrils observed in the brain of aborigines who died of Kuru to the amyloid detectable in the cortex of Alzheimer's patients.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Amyloid beta-Protein Precursor; Brain; Gene Expression; Humans; Kuru; Models, Molecular; Parkinson Disease; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Denaturation; Protein Folding; PrPC Proteins; PrPSc Proteins; tau Proteins; Thermodynamics

Recent data support an involvement of defects in homeostasis of phosphoinositides (PIPs) in the pathophysiology of Parkinson's disease (PD). Genetic mutations have been identified in genes encoding for PIP-regulating and PIP-interacting proteins, that are associated with familial and sporadic PD. Many of these proteins are implicated in vesicular membrane trafficking, mechanisms that were recently highlighted for their close associations with PD. PIPs are phosphorylated forms of the membrane phospholipid, phosphatidylinositol. Their composition in the vesicle's membrane of origin, as well as membrane of destination, controls vesicular membrane trafficking. We review the converging evidence that points to the involvement of PIPs in PD. The review describes PD- and PIP-associated proteins implicated in clathrin-mediated endocytosis and autophagy, and highlights the involvement of α-synuclein in these mechanisms.

Topics: alpha-Synuclein; Autophagy; Endocytosis; Humans; Parkinson Disease; Phosphatidylinositols

As per recent reports, there is an association between glucocerebrosidase (Gcase) enzyme and Parkinson's disease (PD). In addition, certain mutations in the Gcase gene (GBA) and the progranulin (PGRN) gene are found to be linked with the imbalance in the levels of Gcase enzyme. This imbalance or decrease or impairment in Gcase activity can lead to Gaucher disease, frontotemporal lobar degeneration (FTLD), dementia, etc. Recent evidences suggest that the drugs used to treat these diseases can be used for PD. The present review has focused on the therapeutic approaches used for diseases linked with Gcase enzyme, which can be used for PD. The review also considered possible target specific novel strategies, which may help to meet the unmet needs in the treatment of PD.

Topics: alpha-Synuclein; Glucosylceramidase; Humans; Lysosomes; Mutation; Parkinson Disease; Progranulins

Parkinson's disease (PD) is considered the most common disorder of synucleinopathy, which is characterised by intracellular inclusions of aggregated and misfolded α-synuclein (α-syn) protein in various brain regions, and the loss of dopaminergic neurons. During the early prodromal phase of PD, synaptic alterations happen before cell death, which is linked to the synaptic accumulation of toxic α-syn specifically in the presynaptic terminals, affecting neurotransmitter release. The oligomers and protofibrils of α-syn are the most toxic species, and their overexpression impairs the distribution and activation of synaptic proteins, such as the SNARE complex, preventing neurotransmitter exocytosis and neuronal synaptic communication. In the last few years, the role of the immune system in PD has been increasingly considered. Microglial and astrocyte activation, the gene expression of proinflammatory factors, and the infiltration of immune cells from the periphery to the central nervous system (CNS) represent the main features of the inflammatory response. One of the actors of these processes is α-syn accumulation. In light of this, here, we provide a systematic review of PD-related α-syn and inflammation inter-players.

Topics: Adaptive Immunity; alpha-Synuclein; Animals; Astrocytes; Biomarkers; Disease Susceptibility; Dopaminergic Neurons; Humans; Immunity, Innate; Microglia; Parkinson Disease; Synapses

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally, DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (αS), a major component of Lewy bodies. DOPAL potently oligomerizes αS, and αS oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward the MAO-catalyzed formation of DOPAL-destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could "freeze" intraneuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with αS, and vice versa, is poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intraneuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.

Topics: Aldehyde Dehydrogenase; Aldehydes; alpha-Synuclein; Animals; Catechols; Dopamine; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Nerve Degeneration; Neurons; Oxidation-Reduction; Parkinson Disease; PC12 Cells; Rats

Molecular studies have provided increasing evidence that Parkinson's disease (PD) is a protein conformational disease, where the spread of alpha-synuclein (ASN) pathology along the neuraxis correlates with clinical disease outcome. Pathogenic forms of ASN evoke oxidative stress (OS), neuroinflammation, and protein alterations in neighboring cells, thereby intensifying ASN toxicity, neurodegeneration, and neuronal death. A number of evidence suggest that homeostasis between bioactive sphingolipids with opposing function-e.g., sphingosine-1-phosphate (S1P) and ceramide-is essential in pro-survival signaling and cell defense against OS. In contrast, imbalance of the "sphingolipid biostat" favoring pro-oxidative/pro-apoptotic ceramide-mediated changes have been indicated in PD and other neurodegenerative disorders. Therefore, we focused on the role of sphingolipid alterations in ASN burden, as well as in a vast range of its neurotoxic effects. Sphingolipid homeostasis is principally directed by sphingosine kinases (SphKs), which synthesize S1P-a potent lipid mediator regulating cell fate and inflammatory response-making SphK/S1P signaling an essential pharmacological target. A growing number of studies have shown that S1P receptor modulators, and agonists are promising protectants in several neurological diseases. This review demonstrates the relationship between ASN toxicity and alteration of SphK-dependent S1P signaling in OS, neuroinflammation, and neuronal death. Moreover, we discuss the S1P receptor-mediated pathways as a novel promising therapeutic approach in PD.

Topics: alpha-Synuclein; Animals; Humans; Lysophospholipids; Molecular Targeted Therapy; Neuroprotection; Parkinson Disease; Signal Transduction; Sphingosine

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease caused by degeneration of dopaminergic neurons in the substantia nigra. Existing pharmaceutical treatments offer alleviation of symptoms but cannot delay disease progression and are often associated with significant side effects. Clinical studies have demonstrated that acupuncture may be beneficial for PD treatment, particularly in terms of ameliorating PD symptoms when combined with anti-PD medication, reducing the required dose of medication and associated side effects. During early stages of PD, acupuncture may even be used to replace medication. It has also been found that acupuncture can protect dopaminergic neurons from degeneration via antioxidative stress, anti-inflammatory, and antiapoptotic pathways as well as modulating the neurotransmitter balance in the basal ganglia circuit. Here, we review current studies and reflect on the potential of acupuncture as a novel and effective treatment strategy for PD. We found that particularly during the early stages, acupuncture may reduce neurodegeneration of dopaminergic neurons and regulate the balance of the dopaminergic circuit, thus delaying the progression of the disease. The benefits of acupuncture will need to be further verified through basic and clinical studies.

Topics: Acupuncture Therapy; alpha-Synuclein; Antiparkinson Agents; Apoptosis; Basal Ganglia; Bibliometrics; Clinical Trials as Topic; Combined Modality Therapy; Dopamine; Dopaminergic Neurons; Humans; Nerve Net; Neuroinflammatory Diseases; Oxidative Stress; Parkinson Disease; Protein Aggregation, Pathological; Treatment Outcome

Topics: alpha-Synuclein; Animals; Dementia; Dopaminergic Neurons; Humans; Interferon-beta; Mice; Mice, Knockout; Nerve Degeneration; Parkinson Disease; Protein Inhibitors of Activated STAT; Signal Transduction

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by degeneration of the substantia nigra pars compacta and by accumulation of α-synuclein in Lewy bodies. PD is caused by a combination of environmental factors and genetic variants. These variants range from highly penetrant Mendelian alleles to alleles that only modestly increase disease risk. Here, we review what is known about the genetics of PD. We also describe how PD genetics have solidified the role of endosomal, lysosomal, and mitochondrial dysfunction in PD pathophysiology. Finally, we highlight how all three pathways are affected by α-synuclein and how this knowledge may be harnessed for the development of disease-modifying therapeutics.

Topics: alpha-Synuclein; Humans; Lysosomes; Parkinson Disease

Parkinson's disease (PD) is a complex neurodegenerative disorder presenting with defining motor features and a variable combination of nonmotor symptoms. There is growing evidence suggesting that hypothalamic involvement in PD may contribute to the pathogenesis of nonmotor symptoms. Initial neuropathologic studies demonstrated histologic involvement of hypothalamic nuclei by Lewy pathology, i.e., neuronal aggregates including Lewy bodies (round eosinophilic inclusions with a halo found in the neuronal perikarya) and other inclusions in neuronal processes such as Lewy neurites. Recent studies using more sensitive immunohistochemistry have shown that synuclein deposition is common in all hypothalamic nuclei and can happen at preclinical stages of the disease. Several neuropathologic changes, including synuclein deposition, neuronal loss, and adaptative morphologic changes, have been described in neurochemically defined specific hypothalamic cell populations with a potential role in the pathogenesis of nonmotor symptoms such as autonomic dysfunction, blood pressure control, circadian rhythms, sleep, and body weight regulation. The clinical implications of these hypothalamic neuropathologic changes are not fully understood and a direct clinical correlation may be challenging due to the multifactorial pathogenesis of the symptomatology and the additional involvement of other peripheral regulatory mechanisms. Future neuropathologic research using histological and functional assessments should establish the potential role of hypothalamic dysfunction on clinical burden, symptomatic therapies, and disease biomarkers in PD.

Topics: alpha-Synuclein; Humans; Lewy Bodies; Neurons; Neuropathology; Parkinson Disease

Lewy bodies are intraneuronal eosinophilic cytoplasmic inclusions, and their presence in the specific areas of the central nervous system defines the so-called Lewy body disorders such as Parkinson's disease and dementia with Lewy bodies. The protein alpha-synuclein is the major component of Lewy bodies and there is evidence suggesting that it is capable of spreading from cell to cell within the central nervous system thereby propagating the pathological process. The olfactory system, particularly the olfactory bulb, is almost always affected in Parkinson's disease and dementia with Lewy bodies. Moreover, in Parkinson's disease, the olfactory bulb is involved by Lewy pathology at very early stages of the disease. The hypothalamus is also compromised by Lewy pathology in the course of Parkinson's disease; however, unlike the olfactory system in which most regions of the primary olfactory cortex become affected, there is a selective vulnerability of certain hypothalamic regions including the tuberomamillary nucleus, the lateral tuberal nucleus, and orexin/hypocretin neurons, while other nuclear groups remain free of Lewy pathology even in the advanced stages of the disease.

Topics: alpha-Synuclein; Humans; Hypothalamus; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Recently, genome-editing technology like clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 has improved the translational gap in the treatments mediated through gene therapy. The advantages of the CRISPR system, such as, work in the living cells and tissues, candidate this technique for the employing in experiments and the therapy of central nervous system diseases. Parkinson's disease (PD) is a widespread, disabling, neurodegenerative disease induced by dopaminergic neuron loss and linked to progressive motor impairment. Pathophysiological basis knowledge of PD has modified the PD classification model and expresses in the sporadic and familial types. Analyses of the earliest genetic linkage have shown in PD the inclusion of synuclein alpha (SNCA) genomic duplication and SNCA mutations in the familial types of PD pathogenesis. This review analyzes the structure, development, and function in genome editing regulated through the CRISPR/Cas9. Also, it explains the genes associated with PD pathogenesis and the appropriate modifications to favor PD. This study follows the direction by understanding the PD linking analyses in which the CRISPR technique is applied. Finally, this study explains the limitations and future trends of CRISPR service in relation to the genome-editing process in PD patients' induced pluripotent stem cells.

Topics: alpha-Synuclein; CRISPR-Cas Systems; Gene Editing; Humans; Neurodegenerative Diseases; Parkinson Disease

Neurodegenerative diseases such as Alzheimer's and Parkinson's remain highly prevalent and incurable disorders. A major challenge in fully understanding and combating the progression of these diseases is the complexity of the network of processes that lead to progressive neuronal dysfunction and death. An ideal therapeutic avenue is conceivably one that could address many if not all of these multiple misregulated mechanisms. Over the years, chemical intervention for the up-regulation of the endogenous posttranslational modification (PTM) O-GlcNAc has been proposed as a potential strategy to slow down the progression of neurodegeneration. Through the development and application of tools that allow dissection of the mechanistic roles of this PTM, there is now a growing body of evidence that O-GlcNAc influences a variety of important neurodegeneration-pertinent mechanisms, with an overall protective effect. As a PTM that is appended onto numerous proteins that participate in protein quality control and homeostasis, metabolism, bioenergetics, neuronal communication, inflammation, and programmed death, O-GlcNAc has demonstrated beneficence in animal models of neurodegenerative diseases, and its up-regulation is now being pursued in multiple clinical studies.

Topics: Acetylglucosamine; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Glycosylation; Humans; N-Acetylglucosaminyltransferases; Parkinson Disease; Protein Processing, Post-Translational; tau Proteins

Parkinson's disease (PD) is a complex and progressive neurodegenerative disorder with a prevalence of approximately 0.5-1% among those aged 65-70 years. Although most of its clinical manifestations are due to a loss of dopaminergic neurons, the PD etiology is largely unknown. PD is caused by a combination of genetic and environmental factors, and the exact interplay between genes and the environment is still debated. Several biological processes have been implicated in PD, including mitochondrial or lysosomal dysfunctions, alteration in protein clearance, and neuroinflammation, but a common molecular mechanism connecting the different cellular alterations remains incompletely understood. Accumulating evidence underlines a significant role of lipids in the pathological pathways leading to PD. Beside the well-described lipid alteration in idiopathic PD, this review summarizes the several lipid alterations observed in experimental models expressing PD-related genes and suggests a possible scenario in relationship to the molecular mechanisms of neuronal toxicity. PD could be considered a lipid-induced proteinopathy, where alteration in lipid composition or metabolism could induce protein alteration-for instance, alpha-synuclein accumulation-and finally neuronal death.

Topics: alpha-Synuclein; Dopaminergic Neurons; Glucosylceramidase; Group VI Phospholipases A2; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lipid Metabolism; Lipids; Lysosomes; Mitochondria; Nerve Degeneration; Parkinson Disease; Protein Kinases; Ubiquitin-Protein Ligases

Parkinson's disease (PD) ranks first in the world as a neurodegenerative movement disorder and occurs most commonly in an idiopathic form. PD patients may have motor symptoms, non-motor symptoms, including cognitive and behavioral changes, and symptoms related to autonomic nervous system (ANS) failures, such as gastrointestinal, urinary, and cardiovascular symptoms. Unfortunately, the diagnostic accuracy of PD by general neurologists is relatively low. Currently, there is no objective molecular or biochemical test for PD; its diagnosis is based on clinical criteria, mainly by cardinal motor symptoms, which manifest when patients have lost about 60-80% of dopaminergic neurons. Therefore, it is urgent to establish a panel of biomarkers for the early and accurate diagnosis of PD. Once the disease is accurately diagnosed, it may be easier to unravel idiopathic PD's pathogenesis, and ultimately, finding a cure. This review discusses several biomarkers' potential to set a panel for early idiopathic PD diagnosis and future directions.

Topics: alpha-Synuclein; Biomarkers; Early Diagnosis; Enteric Nervous System; Exosomes; Feces; Humans; Inflammation; Intestines; Microbiota; Mouth; Organ Specificity; Parkinson Disease; Permeability; Skin

The principal pathogenic event in Parkinson's disease is characterized by the conformational change of α-synuclein, which form pathological aggregates of misfolded proteins, and then accumulate in intraneuronal inclusions causing dopaminergic neuronal loss in specific brain regions. Over the last few years, a revolutionary theory has correlated Parkinson's disease and other neurological disorders with a shared mechanism, which determines α-synuclein aggregates and progresses in the host in a prion-like manner. In this review, the main characteristics shared between α-synuclein and prion protein are compared and the cofactors that influence the remodeling of native protein structures and pathogenetic mechanisms underlying neurodegeneration are discussed.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Humans; Parkinson Disease; Prion Diseases; Protein Aggregates; tau Proteins

The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson's disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of endogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic propagation of α-syn pathology in the context of neuronal vulnerability and highlight the potential utility of novel experimental models of synucleinopathies.

Topics: alpha-Synuclein; Animals; Humans; Parkinson Disease; Prions; Protein Aggregation, Pathological

Parkinson's disease (PD) is one of the most common progressive neurodegenerative diseases. It is characterized neuropathologically by the presence of alpha-synuclein containing Lewy Bodies in the substantia nigra of the brain with loss of dopaminergic neurons in the pars compacta of the substantia nigra. The presence of alpha-synuclein aggregates in the substantia nigra and the enteric nervous system (ENS) drew attention to the possibility of a correlation between the gut microbiota and Parkinson's disease. The gut-brain axis is a two-way communication system, which explains how through the vagus nerve, the gut microbiota can affect the central nervous system (CNS), including brain functions related to the ENS, as well as how CNS can alter various gut secretions and immune responses. As a result, this dysbiosis or alteration in gut microbiota can be an early sign of PD with reported changes in short chain fatty acids, bile acids, and lipids. This gave rise to the use of probiotics and faecal microbiota transplantation as alternative approaches to improve the symptoms of patients with PD. The aim of this review is to discuss investigations that have been done to explore the gastrointestinal involvement in Parkinson's disease, the effect of dysbiosis, and potential therapeutic strategies for PD.

Topics: alpha-Synuclein; Anti-Bacterial Agents; Brain-Gut Axis; Dysbiosis; Fatty Acids, Volatile; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Humans; Lipids; Parkinson Disease; Probiotics

Research has suggested a link between the gut microbiota and Parkinson's Disease (PD), and an early involvement of gastrointestinal dysfunction has been reported in patients. A mechanism review was performed to investigate whether the neurodegenerative cascade begins in the gut; mediated by gut dysbiosis and retrograde transport of α-synuclein. This review provides a summary of microbiome composition associated with PD, and evaluates pathophysiological mechanisms from animal and in vitro models of PD.. A systematic literature search was performed in PubMed; 82 of 299 papers met the inclusion criteria.. All twenty-two human case-control studies demonstrated an altered gut microbiota in PD compared to healthy controls, with results suggesting a proinflammatory phenotype present in PD. A germ-free animal study has demonstrated that gut microbiota are required for microglia activation, α-synuclein pathology and motor deficits. Accumulation of phosphorylated α-synuclein has been observed in the enteric nervous system prior to the onset of motor symptoms in animal models of PD, and there is data to support retrograde transport of α-synuclein from the gut to the brain. Different animal models of PD have demonstrated neuroinflammation, microglial activation and loss of dopaminergic neurons in the brain.. Evidence from this review supports the hypothesis that pathology spreads from the gut to the brain. Future animal studies using oral LPS or microbiota transplants from human PD cases could provide further insight into the entire mechanism. Prospective longitudinal microbiome studies and novel modelling approaches could help to identify functional dysbiosis and early biomarkers for PD.

Topics: alpha-Synuclein; Animals; Gastrointestinal Microbiome; Humans; Parkinson Disease

A neuropathological hallmark of Parkinson's disease (PD) is the cerebral deposition of abnormally aggregated α-synuclein (αSyn). PD-associated αSyn (αSyn

Topics: alpha-Synuclein; Animals; Brain; Enteric Nervous System; Gastrointestinal Tract; Humans; Mice; Parkinson Disease; Prion Proteins; Prions; Protein Aggregation, Pathological

Parkinson's disease (PD) is the second most common neurodegenerative disease amongst the middle‑aged and elderly populations. Several studies have confirmed that the microbiota‑gut‑brain axis (MGBA) serves a key role in the pathogenesis of PD. Changes to the gastrointestinal microbiome (GM) cause misfolding and abnormal aggregation of α‑synuclein (α‑syn) in the intestine. Abnormal α‑syn is not eliminated via physiological mechanisms and is transported into the central nervous system (CNS) via the vagus nerve. The abnormal levels of α‑syn aggregate in the substantia nigra pars compacta, not only leading to the formation of eosinophilic Lewis Bodies in the cytoplasm and mitochondrial dysfunction in dopaminergic (DA) neurons, but also leading to the stimulation of an inflammatory response in the microglia. These pathological changes result in an increase in oxidative stress (OS), which triggers nerve cell apoptosis, a characteristic of PD. This increase in OS further oxidizes and intensifies abnormal aggregation of α‑syn, eventually forming a positive feedback loop. The present review discusses the abnormal accumulation of α‑syn in the intestine caused by the GM changes and the increased levels of α‑syn transport to the CNS via the MGBA, resulting in the loss of DA neurons and an increase in the inflammatory response of microglial cells in the brain of patients with PD. In addition, relevant clinical therapeutic strategies for improving the GM and reducing α‑syn accumulation to relieve the symptoms and progression of PD are described.

Topics: Aged; alpha-Synuclein; Bacteria; Brain; Brain-Gut Axis; Disease Progression; Dopaminergic Neurons; Dysbiosis; Gastrointestinal Microbiome; Humans; Microglia; Middle Aged; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease

Parkinson's disease (PD) is a movement disorder associated with severe loss of mainly dopaminergic neurons in the substantia nigra. Pathological hallmarks include Lewy bodies, and loss of neuromelanin, due to degeneration of neuromelanin-containing dopaminergic neurons. Despite being described over 200 years ago, the etiology of PD remains unknown. Here, we highlight the roles of reactive oxygen species (ROS), iron, alpha synuclein (α-syn) and neuromelanin in a toxic feedback loop culminating in neuronal death and spread of the disease. Dopaminergic neurons are particularly vulnerable due to decreased antioxidant concentration with aging, constant exposure to ROS and presence of neurotoxic compounds (e.g. ortho-quinones). ROS and iron increase each other's levels, creating a state of oxidative stress. α-Syn aggregation is influenced by ROS and iron but also increases ROS and iron via its induced mitochondrial dysfunction and ferric-reductase activity. Neuromelanin's binding affinity is affected by increased ROS and iron. Furthermore, during neuronal death, neuromelanin is degraded in the extracellular space, releasing its bound toxins. This cycle of events continues to neighboring neurons in the form of a toxic loop, causing PD pathology. The increase in ROS and iron may be an important target for therapies to disrupt this toxic loop, and therefore diets rich in certain 'nutraceuticals' may be beneficial. Turmeric is an attractive candidate, as it is known to have anti-oxidant and iron chelating properties. More studies are needed to test this theory and if validated, this would be a step towards development of lifestyle-based therapeutic modalities to complement existing PD treatments.

Topics: alpha-Synuclein; Animals; Autophagy; Brain Chemistry; Curcuma; Dopamine; Dopaminergic Neurons; Feedback, Physiological; Ferroptosis; Homeostasis; Humans; Iron; Melanins; Mice; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Phytotherapy; Protein Aggregation, Pathological; Reactive Oxygen Species; Substantia Nigra

Alpha-synuclein aggregation and mitochondrial dysfunction are main pathological hallmarks of Parkinson's disease (PD) and several other neurodegenerative diseases, collectively known as synucleinopathies. However, increasing evidence suggests that they may not be sufficient to cause PD. Here we propose the role of hypoxia as a missing link that connects the complex interplay between alpha-synuclein biochemistry and pathology, mitochondrial dysfunctions and neurodegeneration in PD. We review the partly conflicting literature on alpha-synuclein binding to membranes and mitochondria and its impact on mitochondrial functions. From there, we focus on adverse changes in cellular environments, revolving around hypoxic stress, that may trigger or facilitate PD progression. Inter-dependent structural re-arrangements of mitochondrial membranes, including increased cytoplasmic exposure of mitochondrial cardiolipins and changes in alpha-synuclein localization and conformation are discussed consequences of such conditions. Enhancing cellular resilience could be an integral part of future combination-based therapies of PD. This may be achieved by boosting the capacity of cellular and specifically mitochondrial processes to regulate and adapt to altered proteostasis, redox, and inflammatory conditions and by inducing protective molecular and tissue re-modelling.

Topics: alpha-Synuclein; Cardiolipins; Humans; Hypoxia; Inflammation; Mitochondria; Mitochondrial Membranes; Oxidation-Reduction; Parkinson Disease; Proteostasis; Synucleinopathies

α-Synuclein (α-Syn) is a small cytosolic protein associated with a range of cellular compartments, including synaptic vesicles, the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. In addition to its physiological role in regulating presynaptic function, the protein plays a central role in both sporadic and familial Parkinson's disease (PD) via a gain-of-function mechanism. Because of this, several recent strategies propose to decrease α-Syn levels in PD patients. While these therapies may offer breakthroughs in PD management, the normal functions of α-Syn and potential side effects of its depletion require careful evaluation. Here, we review recent evidence on physiological and pathological roles of α-Syn in regulating activity-dependent signal transduction and gene expression pathways that play fundamental role in synaptic plasticity.

Topics: alpha-Synuclein; Gene Expression; Humans; Neuronal Plasticity; Parkinson Disease; Signal Transduction

Parkinson's disease (PD) is a movement disorder identified more than 200 years ago; today it is defined by specific motor symptoms that together receive the name of parkinsonism. PD diagnosis is reached with the full parkinsonian syndrome, but in recent years, a series of non-motor symptoms have arisen as intrinsic components of PD. These non-motor symptoms are variable, creating a widely heterogenous disease presentation. Some non-motor symptoms appear in late disease stages and are explained as the natural progression of PD pathology into other brain centres, including the frontal cortex. Other symptoms can appear a decade or earlier preceding PD diagnosis, particularly hyposmia (loss of smell) and constipation. These early symptoms and the accompanying protein pathology have stimulated a lively conversation about the origin and nature of PD and other related conditions: some authors propose that PD starts in the olfactory mucosa and the gut due to direct exposure to toxins or pathogens. This pathology then travels by anatomically interconnected networks to the midbrain to cause motor symptoms and the cortex to cause late complications. Other models propose that PD develops in multiple independent foci that do not require pathology spread. We will review these hypotheses in the context of recent developments regarding the spread of amyloids and propose a mixed model where a multifocal origin explains the variable presentation of PD, while cell-to-cell spread explains stereotypical disease progression.

Topics: alpha-Synuclein; Disease Progression; Dopamine; Frontal Lobe; Humans; Olfactory Mucosa; Parkinson Disease; Parkinsonian Disorders; Serum Amyloid A Protein

Parkinson's disease (PD) is a complex neurodegenerative disorder with no cure in sight. Clinical challenges of the disease include the inability to make a definitive diagnosis at the early stages and difficulties in predicting the disease progression. The unmet demand to identify reliable biomarkers for early diagnosis and management of the disease course of PD has attracted a lot of attention. However, only a few reported candidate biomarkers have been tried in clinical practice at the present time. Studies on PD biomarkers have often overemphasized the discovery of novel identity, whereas efforts to further evaluate such candidates are rare. Therefore, we update the new development of biomarker discovery in PD and discuss the standard process in the evaluation and assessment of the diagnostic or prognostic value of the identified potential PD biomarkers in this review article. Recent developments in combined biomarkers and the current status of clinical trials of biomarkers as outcome measures are also discussed. We believe that the combination of different biomarkers might enhance the specificity and sensitivity over a single measure that might not be sufficient for such a multiplex disease.

Topics: alpha-Synuclein; Biomarkers; Extracellular Vesicles; Humans; Inflammation; MicroRNAs; Parkinson Disease

Synucleinopathies are neurodegenerative diseases characterized by the accumulation of either neuronal/axonal or glial insoluble proteinaceous aggregates mainly composed of α-synuclein (α-syn). Among them, the most common disorders are Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and some forms of familial parkinsonism. Both α-syn fibrils and oligomers have been found to exert toxic effects on neurons or oligodendroglial cells, can activate neuroinflammatory responses, and mediate the spreading of α-syn pathology. This poses the question of which is the most toxic α-syn species. What is worst, α-syn appears as a very peculiar protein, exerting multiple physiological functions in neurons, especially at synapses, but without acquiring a stable tertiary structure. Its conformation is particularly plastic, and the protein can exist in a natively unfolded state (mainly in solution), partially α-helical folded state (when it interacts with biological membranes), or oligomeric state (tetramers or dimers with debated functional profile). The extent of α-syn expression impinges on the resilience of neuronal cells, as multiplications of its gene locus, or overexpression, can cause neurodegeneration and onset of motor phenotype. For these reasons, one of the main challenges in the field of synucleinopathies, which still nowadays can only be managed by symptomatic therapies, has been the development of strategies aimed at reducing α-syn levels, oligomer formation, fibrillation, or cell-to-cell transmission. This review resumes the therapeutic approaches that have been proposed or are under development to counteract α-syn pathology by direct targeting of this protein and discuss their pros and cons in relation to the current state-of-the-art α-syn biology.

Topics: alpha-Synuclein; Animals; Genetic Therapy; Humans; Immunotherapy; Intermediate Filament Proteins; Molecular Targeted Therapy; Multiple System Atrophy; Parkinson Disease; Synapses

The accumulation and misfolding of α-synuclein (α-syn) represent the main pathological hallmark of PD. Overexpression of α-syn and failure of cellular protein degradation systems play a major role in α-syn aggregation. The discovery of PD-associated genes related to the autophagic-lysosomal pathway, such as VPS35, LRRK2, GBA1, SMPD1, GALC, ASAH1, SCARB2, CTSD, CTSB, and GLA, confirms the involvement of cellular clearance systems dysfunction in PD pathogenesis. Of importance, lysosomal enzyme activity is altered both in genetic and sporadic PD. Decreased lysosomal enzymes activities were measured in the same brain regions where α-syn accumulates, suggesting that a crosstalk between α-syn aggregation and autophagic-lysosomal impairment may exist. The understanding of autophagic-lysosomal pathway dysfunctions' role in the pathogenesis and progression of synucleinopathies opened new perspectives for novel possible therapeutic strategies. In this article, the evidences and mechanisms of the reciprocal relation between autophagic-lysosomal pathway impairment and misfolded α-syn aggregation and propagation are reviewed, together with the most promising compounds targeting autophagic-lysosomal pathway restoration as a disease-modifying strategy for PD treatment. © 2019 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Autophagy; Brain; Glucosylceramidase; Humans; Lysosomes; Parkinson Disease

Parkinson's disease (PD) is one of the most common forms of neurodegenerative disorders, and its etiology remains unclear. Single nucleotide polymorphisms (SNPs) of alpha-synuclein (SNCA) have been found to be significantly associated with PD risk. In particular, the variant rs11931074 was found in one meta-analysis to appear to play a role in the occurrence of PD. This finding has been questioned in subsequent studies, however. The aim of this study was to determine the relationship between PD risk and rs11931074 polymorphism.. We performed a systematic online search, including PubMed, Web of Science, EMBASE, Cochrane Library, and CNKI (China National Knowledge Infrastructure), aiming to identify case-control studies looking at the role of rs11931074 in PD. We performed calculations of pooled odds ratio (OR) and 95% confidence interval (95% CI) to assess the associations, and subgroup meta-analyses to verify differences between various ethnicities of different study populations.. A total of 13 studies involving 13,403 cases and 28,408 controls met the inclusion criteria after assessment by two reviewers. Overall, there exists significant associations between SNCA rs11931074 polymorphism and the risk of PD under five genetic models (allele contrast model: T vs. G, OR = 1.28, 95% CI = 1.12-1.45, P = 0.0001; homozygote model: TG vs. GG, OR = 1.55, 95% CI = 1.17-2.05, P = 0.002; heterozygote model (TT vs. GG, OR = 1.23, 95% CI = 1.05-1.42, P = 0.009; dominant model: TG+TT vs. GG: OR = 1.25, 95% CI = 1.05-1.50, P = 0.01 and recessive model: TT vs. TG+GG: OR = 1.40, 95% CI = 1.18-1.68, P = 0.0002). When ethnicities were stratified, significant associations were found in the allelic, homozygote, and recessive models for Asians, and in the allelic model for Caucasians.. SNCA rs11931074 polymorphism is found to be associated with PD risk and this risk appears to be influenced by genetic status and ethnicity.

Topics: alpha-Synuclein; Gene Expression; Genetic Predisposition to Disease; Humans; Parkinson Disease; Polymorphism, Single Nucleotide

The discovery that patients with Gaucher Disease (GD), a rare lysosomal storage disorder, were developing symptoms similar to Parkinson's disease (PD) led to investigation of the relationship between the two seemingly unrelated pathologies. GD, an autosomal recessive disorder, is the result of a biallelic mutation in the gene GBA1, which encodes for the enzyme glucocerebrosidase (GCase). Since the observation of its relation to PD, GBA1 mutations have become recognized as the most common genetic risk factor for development of synucleinopathies such as PD and dementia with Lewy bodies. Although the exact mechanism by which GBA1 mutations promote PD is unknown, current understanding suggests that impaired GCase inhibits lysosomal activity and decreases the overall ability of the cell to degrade proteins, specifically the neuronal protein α-synuclein. Decreased elimination of α-synuclein can lead to its abnormal accumulation and aggregation, an important component of PD development. Further understanding of how decreased GCase activity increases risk for α-synuclein pathology can assist with the development of clinical biomarkers for early detection of synucleinopathies, as well as promote novel treatments tailored for people with a GBA1 mutation. Historically, α-synuclein has not been a reliable biomarker for PD. However, recent research on α-synuclein content within exosomes, which are small vesicles released by cells that carry specific cellular cargo, has yielded encouraging results. Moreover, decreased GCase activity has been shown to influence exosomal contents. Exosomes have emerged as a promising new avenue for the identification of novel biomarkers and therapeutic targets aimed at improving neuronal GCase function and limiting the development of synucleinopathies.

Topics: alpha-Synuclein; Animals; Biomarkers; Clinical Trials as Topic; Gaucher Disease; Glucosylceramidase; Humans; Lysosomes; Mice; Mutation; Parkinson Disease; Synucleinopathies

In recent years, multiple lines of evidence from human genetic and molecular studies have highlighted the importance of the autophagy lysosomal pathway (ALP) in Parkinson's disease (PD). Genes such as GBA and LRRK2, which harbor some of the most common mutations associated with PD, have essential roles in the ALP. α-synuclein, encoded by the SNCA gene, is degraded mainly by the ALP, and mutations/multiplications in SNCA may lead to impairment of chaperone mediated autophagy or other ALP functions. Numerous other PD-related genes, such as PRKN, PINK1, TMEM175, SMPD1, CTSD, CTSB and many more, have also been reported to have important roles in the ALP. Understanding the relationship between ALP impairment and PD pathogenesis may be crucial for uncovering the mechanisms underlying PD, and for the development of long-awaited neuroprotective therapies. In this review, we will discuss the data linking the ALP to PD (other, atypical forms of Parkinsonism, will not be discussed in this review). We will focus on evidence from studies on specific genes and proteins, their roles in the ALP, and the potential mechanisms underlying the involvement of these genes in PD.

Topics: alpha-Synuclein; Autophagy; Glucosylceramidase; Humans; Lysosomes; Metabolic Networks and Pathways; Parkinson Disease

Parkinson disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms which relentlessly and progressively lead to substantial disability and economic burden. Pathologically, these symptoms follow the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) associated with abnormal α-synuclein (α-Syn) deposition as cytoplasmic inclusions called Lewy bodies in pigmented brainstem nuclei, and in dystrophic neurons in striatal and cortical regions (Lewy neurites). Pharmacotherapy for PD focuses on improving quality of life and primarily targets dopaminergic pathways. Dopamine acts through two families of receptors, dopamine D1-like and dopamine D2-like; dopamine D3 receptors (D3R) belong to dopamine D2 receptor (D2R) family. Although D3R's precise role in the pathophysiology and treatment of PD has not been determined, we present evidence suggesting an important role for D3R in the early development and occurrence of PD. Agonist activation of D3R increases dopamine concentration, decreases α-Syn accumulation, enhances secretion of brain derived neurotrophic factors (BDNF), ameliorates neuroinflammation, alleviates oxidative stress, promotes neurogenesis in the nigrostriatal pathway, interacts with D1R to reduce PD associated motor symptoms and ameliorates side effects of levodopa (L-DOPA) treatment. Furthermore, D3R mutations can predict PD age of onset and prognosis of PD treatment. The role of D3R in PD merits further research. This review elucidates the potential role of D3R in PD pathogenesis and therapy.

Topics: alpha-Synuclein; Animals; Dopamine; Dopaminergic Neurons; Humans; Parkinson Disease; Receptors, Dopamine D3

The gut-brain axis is a hot topic in Parkinson's disease. In an attempt to decipher its role in the disease pathogenesis, several animal models have been developed. Most of these models tried to reproduce Braak's hypothesis by showing that the pathological process could spread from the gut to the brain (bottom-up scenario). Interestingly, others groups showed that a top-down scenario could also occur and that 6-hydroxydopamine-induced nigrostriatal denervation was sufficient to induce significant changes in the gastrointestinal tract. Aside from this toxic approach, the article by O'Donovan and colleagues in this edition of Neurogastroenterology and Motility showed that bilateral nigral injection of adeno-associated virus (AAV)-alpha-synuclein in rats was accompanied by changes in the enteric nervous system and the gut microbiota, which occurred without any apparent brain-to-gut spread of human injected alpha-synuclein. Some changes observed in the gastrointestinal tract of animals injected with AAV-alpha-synuclein were in line with previous observations in Parkinson's disease patients, including increased expression of glial markers, swollen tyrosine hydroxylase-positive varicosities in the submucosal plexus, and decreases in Faecalibacterium and Lachnospiraceae. These findings suggest that, in addition to gut-brain pathways, the brain-to-gut communication may also be involved in Parkinson's disease pathophysiology. In this mini-review, we describe the strengths and limitations of the existing studies on the gut-brain axis in experimental models of parkinsonism and discuss an alternative hypothesis in which the central and enteric nervous system would evolve separately during disease progression.

Topics: alpha-Synuclein; Animals; Brain; Enteric Nervous System; Gastrointestinal Microbiome; Humans; Parkinson Disease

α-Synuclein is a hallmark amyloidogenic protein component of the Lewy bodies (LBs) present in dopaminergic neurons affected by Parkinson's disease (PD). Despite an enormous increase in emerging knowledge, the mechanism(s) of α-synuclein neurobiology and crosstalk among pathological events that are critical for PD progression remains enigmatic, creating a roadblock for effective intervention strategies. One confounding question is about the potential link between α-synuclein toxicity and genome instability in PD. We previously reported that pro-oxidant metal ions, together with reactive oxygen species (ROS), act as a "double whammy" in dopaminergic neurons by not only inducing genome damage but also inhibiting their repair. Our recent studies identified a direct role for chromatin-bound, oxidized α-synuclein in the induction of DNA strand breaks, which raised the question of a paradoxical role for α-synuclein's DNA binding in neuroprotection versus neurotoxicity. Furthermore, recent advances in our understanding of α-synuclein mediated mitochondrial dysfunction warrants revisiting the topics of α-synuclein pathophysiology in order to devise and assess the efficacy of α-synuclein-targeted interventions. In this review article, we discuss the multi-faceted neurotoxic role of α-synuclein in the nucleus and mitochondria with a particular emphasis on the role of α-synuclein in DNA damage/repair defects. We utilized a protein-DNA binding simulation to identify potential residues in α-synuclein that could mediate its binding to DNA and may be critical for its genotoxic functions. These emerging insights and paradigms may guide new drug targets and therapeutic modalities.

Topics: alpha-Synuclein; Animals; Chromatin; DNA Damage; Dopaminergic Neurons; Humans; Mitochondria; Parkinson Disease

Several studies have investigated the correlation between single nucleotide polymorphism (SNP) rs356220 in the α-synuclein (SNCA) gene and Parkinson's disease (PD) with inconsistent results. Herein, a meta-analysis was conducted to ascertain the association of the SNCA rs356220 polymorphism with the risk of PD. Six eligible articles involving 5333 PD cases and 5477 controls were included in this meta-analysis. The pooled odds ratios (OR) and 95 % confidence interval (CI) were calculated to estimate the association. The fixed or random effect was selected based on the homogeneity among studies. Heterogeneity was detected by I

Topics: alpha-Synuclein; Case-Control Studies; Gene Expression; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Parkinson Disease; Risk Factors

Neurodegenerative diseases are a leading apprehension in underdeveloped and developed countries. The advancement of medical science is synonymous with an increase in life expectancy, which results in an aging population. Neurodegenerative diseases in the older population are on the rise globally. This review sums up the novel therapeutic approaches for Alzheimer's and Parkinson's disease. Although most neurodegenerative diseases occur due to the accumulation of misfolded proteins, the mechanisms are not completely understood. Currently, only prophylactic therapies are available and none are preventive in nature. The World Health Organisation estimates that neurodegenerative diseases that cause cognitive and motor impairments will be the second most ubiquitous cause of death in the next decade, hence the need for novel therapeutic targets for these diseases is demanded. In Alzheimer's, β-amyloid and tau proteinopathies are prevalent, whereas a prion-like increase of α- synuclein is the characteristic trait of Parkinson's disease.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Humans; Parkinson Disease; tau Proteins

Topics: alpha-Synuclein; Animals; Cognition; gamma-Aminobutyric Acid; Humans; Parkinson Disease; Smad3 Protein; Synaptic Transmission

The pathogenesis of Parkinson's disease (PD), the second most common neurodegenerative disorder, is complex and involves the impairment of crucial intracellular physiological processes. Importantly, in addition to abnormal α-synuclein aggregation, the dysfunction of various mitochondria-dependent processes has been prominently implicated in PD pathogenesis. Besides the long-known loss of the organelles' bioenergetics function resulting in diminished ATP synthesis, more recent studies in the field have increasingly focused on compromised mitochondrial quality control as well as impaired biochemical processes specifically localized to ER-mitochondria interfaces (such as lipid biosynthesis and calcium homeostasis). In this review, we will discuss how dysregulated mitochondrial crosstalk with other organelles contributes to PD pathogenesis.

Topics: alpha-Synuclein; Endoplasmic Reticulum; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lysosomes; Mitochondria; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Proton-Translocating ATPases; Ubiquitin-Protein Ligases; Vesicular Transport Proteins

The discovery of genes involved in familial as well as sporadic forms of Parkinson disease (PD) constitutes an important milestone in understanding this disorder's pathophysiology and potential treatment. Among these genes, GBA1 is one of the most common and well-studied, but it is still unclear how mutations in GBA1 translate into an increased risk for developing PD. In this review, we provide an overview of the biochemical and structural relationship between GBA1 and PD to help understand the recent advances in the development of PD therapies intended to target this pathway.

Topics: alpha-Synuclein; Genetic Predisposition to Disease; Glucosylceramidase; Heterozygote; Humans; Mutation; Parkinson Disease; Protein Structure, Quaternary

With the increasing prevalence of Parkinson's disease (PD), there is an immediate need to interdict disease signs and symptoms. In recent years this need was met through therapeutic approaches focused on regenerative stem cell replacement and alpha-synuclein clearance. However, neither have shown long-term clinical benefit. A novel therapeutic approach designed to affect disease is focused on transforming the brain's immune microenvironment. As disordered innate and adaptive immune functions are primary components of neurodegenerative disease pathogenesis, this has emerged as a clear opportunity for therapeutic development. Interventions that immunologically restore the brain's homeostatic environment can lead to neuroprotective outcomes. These have recently been demonstrated in both laboratory and early clinical investigations. To these ends, efforts to increase the numbers and function of regulatory T cells over dominant effector cells that exacerbate systemic inflammation and neurodegeneration have emerged as a primary research focus. These therapeutics show broad promise in affecting disease outcomes beyond PD, such as for Alzheimer's disease, stroke and traumatic brain injuries, which share common neurodegenerative disease processes.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Humans; Immunologic Factors; Immunotherapy; Inflammation; Parkinson Disease

Parkinson's disease (PD) is characterised by selective and severe degeneration of the substantia nigra pars compacta and the locus coeruleus (LC), which underlies the most prominent symptoms. Although α-synuclein accumulation has long been established to play a causal role in the disease, it alone cannot explain the selective degenerative pattern. Recent evidence shows that the selective vulnerability could arise due to the large presence of cytosolic catecholamines and Ca

Topics: alpha-Synuclein; Humans; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Ubiquitin-Protein Ligases

Parkinson's disease has been considered as a motor neuron disease with dopamine (DA) deficit caused by neuronal loss in the substantia nigra, but now proposed as a multi-system disorder associated with α-synuclein accumulation in neuronal and non-neuronal systems. Neuroprotection in Parkinson's disease has intended to halt or reverse cell death of nigro-striatal DA neurons and prevent the disease progression, but clinical studies have not presented enough beneficial results, except the trial of rasagiline by delayed start design at low dose of 1 mg/day only. Now strategy of disease-modifying therapy should be reconsidered taking consideration of accumulation and toxicity of α-synuclein preceding the manifest of motor symptoms. Hitherto neuroprotective therapy has been aimed to mitigate non-specific risk factors; oxidative stress, mitochondrial dysfunction, apoptosis, deficits of neurotrophic factors (NTFs), inflammation and accumulation of pathogenic protein. Future disease-modify therapy should target more specified pathogenic factors, including deregulated mitochondrial homeostasis, deficit of NTFs and α-synuclein toxicity. Selegiline and rasagiline, inhibitors of type B monoamine oxidase, have been proved to exhibit potent neuroprotective function: regulation of mitochondrial apoptosis system, maintenance of mitochondrial function, increased expression of genes coding antioxidant enzymes, anti-apoptotic Bcl-2 and pro-survival NTFs, and suppression of oligomerization and aggregation of α-synuclein and the toxicity in cellular and animal experiments. However, the present available pharmacological therapy starts too late to reverse disease progression, and future disease-modifying therapy should include also non-pharmacological complementary therapy during the prodromal stage.

Topics: alpha-Synuclein; Animals; Apoptosis; Homeostasis; Humans; Indans; Mitochondria; Monoamine Oxidase Inhibitors; Parkinson Disease; Selegiline

The identification of reliable biomarkers of Parkinson's disease (PD) is a pivotal step in the introduction of causal therapies. Saliva is a biofluid which may be involved in synuclein pathology in PD. We have reviewed current studies on salivary proteins and compounds in PD patients and healthy controls, and their potential application as biomarkers. A systematic literature search of the Pubmed and Scopus databases was performed. A total of 198 studies were screened, of which 20 were included in our qualitative analysis. We conclude that the oligomeric form of salivary alpha synuclein is higher in PD patients, and that this may serve as a potential biomarker of PD. Salivary DJ-1 concentrations fail to differentiate PD patients from controls. Other enzymes and substances (heme oxygenase-1, nitric oxide, acetylcholinesterase) have been assessed in single studies. Salivary cortisol levels are higher in PD than in healthy subjects. Further validation of these findings is needed. Saliva may be a promising source of biomarkers in PD.

Topics: alpha-Synuclein; Biomarkers; Humans; Mouth; Parkinson Disease; Saliva

The involvement of copper in numerous physiological processes makes this metal ion essential for human life. Alterations in copper homeostasis might have deleterious consequences, and several neurodegenerative disorders, including Parkinson's disease (PD), have been associated with impaired copper levels. In the present review, we describe the molecular mechanisms through which copper can exert its toxicity, by considering how it can interfere with other cellular processes known to play a role in PD, such as dopamine metabolism, oxidative stress, and α-synuclein aggregation. The recent experimental evidence that associates copper deficiency and the formation of superoxide dismutase 1 (SOD1) aggregates with the progression of PD is also discussed together with its therapeutic implication. Overall, the recent discoveries described in this review show how either copper deficiency or excessive levels can promote detrimental effects, highlighting the importance of preserving copper homeostasis and opening unexplored therapeutic avenues in the definition of novel disease-modifying drugs.

Topics: alpha-Synuclein; Animals; Copper; Disease Progression; Dopamine; Homeostasis; Humans; Ions; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Superoxide Dismutase-1

While the initial causes of Parkinson's disease (PD) are not clearly defined, iron deposition has long been implicated in the pathogenesis of PD. The substantia nigra of PD patients, where the selective loss of dopaminergic neurons occurs, show a fairly selective and significant elevation in iron contents. However, the question remains whether iron deposition represents the initiation cause or merely the consequence of nigral degeneration. Here, we describe existing findings regarding the interaction of iron with neuromelanin and alpha synuclein, the iron deposition in experimental animal model of PD and sporadic and familial PD patients, and the treatment option involving the use of iron chelators for targeting the aberration of iron level in brain. This review may provide us a better understanding of the role of iron in PD to address the question of cause or consequence.

Topics: alpha-Synuclein; Animals; Humans; Iron; Iron Chelating Agents; Melanins; Parkinson Disease; Substantia Nigra

To date, there have been several reports about the genes associated with familial Parkinson's disease. These genes are classified following the PARK nomenclature. The prevalence of these genes varies between countries. Moreover, each gene is associated with different symptoms during disease progression. In this review, we will summarize the clinical findings and molecular functions, with a focus on alpha-synuclein, along with recent discoveries and will try to associate them with sporadic Parkinson's disease.

Topics: alpha-Synuclein; Humans; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Although the standard dopamine replacement therapy can alleviate motor symptoms, presently there is no available treatment to stop or reverse disease progression. Thus, there is an urgent need for the development of novel disease-modifying therapies to prevent the accumulation of cytotoxic α-synuclein (αS), a protein involved in PD pathogenesis, in the nervous system. Furthermore, emerging evidence suggests that the toxic αS species can move from one cell to another, thereby affecting the normal physiological state of the neighboring cells in a prion-like manner. The transmissible, extracellular αS is considered to be an ideal target for the disease-modifying treatments including antibody-based therapy. In this review, we will describe the molecular structure and functions of αS, its relevance to PD pathogenesis, and will discuss the current status and future perspectives of disease-modifying strategies targeting αS in PD.

Topics: alpha-Synuclein; Dopamine; Humans; Neurodegenerative Diseases; Parkinson Disease; Prions

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by motor symptoms such as tremor, slowness of movement, rigidity, and postural instability, as well as non-motor features like sleep disturbances, loss of ability to smell, depression, constipation, and pain. Motor symptoms are caused by depletion of dopamine in the striatum due to the progressive loss of dopamine neurons in the substantia nigra pars compacta. Approximately 10% of PD cases are familial arising from genetic mutations in α-synuclein, LRRK2, DJ-1, PINK1, parkin, and several other proteins. The majority of PD cases are, however, idiopathic, i.e., having no clear etiology. PD is characterized by progressive accumulation of insoluble inclusions, known as Lewy bodies, mostly composed of α-synuclein and membrane components. The cause of PD is currently attributed to cellular proteostasis deregulation and mitochondrial dysfunction, which are likely interdependent. In addition, neuroinflammation is present in brains of PD patients, but whether it is the cause or consequence of neurodegeneration remains to be studied. Rodents do not develop PD or PD-like motor symptoms spontaneously; however, neurotoxins, genetic mutations, viral vector-mediated transgene expression and, recently, injections of misfolded α-synuclein have been successfully utilized to model certain aspects of the disease. Here, we critically review the advantages and drawbacks of rodent PD models and discuss approaches to advance pre-clinical PD research towards successful disease-modifying therapy. © 2020 The Authors.

Topics: alpha-Synuclein; Animals; Corpus Striatum; Dopaminergic Neurons; Drug Evaluation, Preclinical; Forecasting; Genome-Wide Association Study; Histological Techniques; Humans; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neuroprotective Agents; Neurotoxins; Parkinson Disease; Parkinsonian Disorders; Pesticides; Protein Aggregation, Pathological; Rats; Substantia Nigra; Synucleinopathies

Parkinson's disease is a common neurodegenerative disorder that presents with nonmotor and motor symptoms. The nonmotor manifestations of Parkinson's disease often begin years before the motor symptoms. Autopsy studies, including both Parkinson's disease patients and matched controls, demonstrated that α-synuclein aggregates in Parkinson's disease patients can be found in both the substantia nigra and the enteric nervous system. Therefore, it has been hypothesized that the pathological process that leads eventually to Parkinson's disease might initially take place in the enteric nervous system years before the appearance of motor features. The gut microbiome plays essential roles in the development and maintenance of different body systems. Dysbiosis of the normal gut microbiome is thought to be associated with pathophysiologic changes not only in the gastrointestinal system itself but also in the enteric and central nervous systems. These changes are thought to ultimately cause loss of dopaminergic neurons via various mechanisms including the release of neurotoxins into the systemic circulation, decreased production of neuroprotective factors, and triggering inflammatory and autoimmune responses. In this review, we review the gut microbiome changes in Parkinson's disease and discuss the mechanisms by which gut microbiome dysbiosis may be a contributing factor to the pathophysiology of Parkinson's disease. © 2020 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Dysbiosis; Gastrointestinal Microbiome; Humans; Parkinson Disease

Ironically, population aging which is considered a public health success has been accompanied by a myriad of new health challenges, which include neurodegenerative disorders (NDDs), the incidence of which increases proportionally to age. Among them, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common, with the misfolding and the aggregation of proteins being common and causal in the pathogenesis of both diseases. AD is characterized by the presence of hyperphosphorylated τ protein (tau), which is the main component of neurofibrillary tangles (NFTs), and senile plaques the main component of which is β-amyloid peptide aggregates (Aβ). The neuropathological hallmark of PD is α-synuclein aggregates (α-syn), which are present as insoluble fibrils, the primary structural component of Lewy body (LB) and neurites (LN). An increasing number of non-invasive PET examinations have been used for AD, to monitor the pathological progress (hallmarks) of disease. Notwithstanding, still the need for the development of novel detection tools for other proteinopathies still remains. This review, although not exhaustively, looks at the timeline of the development of existing tracers used in the imaging of Aβ and important moments that led to the development of these tracers.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Brain; Humans; Parkinson Disease; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals; tau Proteins

Topics: alpha-Synuclein; Animals; Brain; Gaucher Disease; Genetic Therapy; Glucosylceramidase; Humans; Molecular Targeted Therapy; Mutation; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Despite its high frequency the etiology is still unclear; several lines of evidence show that an inflammatory process is implicated in the pathogenesis of this disorder; where activation of brain microglia plays a central role in the damage of dopaminergic neurons of the substantia nigra. Such inflammation has been attributed to the toxic effect of aggregated α-synuclein; however, evidence also implicates an altered gut microbiota (dysbiosis) through the systemic release of endotoxins such as lipopolysaccharide and other metabolic products. This exposure may be enhanced by increased permeability of the intestinal ("leaky gut") and the blood brain barrier; enhancing the entrance of microbiota-produced substances into the central nervous system. In this manuscript, we explore the evidence from clinical and basic science implicating microglia activation by gut dysbiosis and how this phenomenon may impact in the symptomatology and progression of PD.

Topics: alpha-Synuclein; Dysbiosis; Gastrointestinal Microbiome; Humans; Parkinson Disease; Substantia Nigra

Fibrils of alpha-synuclein are significant components of cellular inclusions associated with several neuropathological disorders including Parkinson's disease, multiple system atrophy and dementia with Lewy bodies. In recent years, technological advances in the field of transmission electron microscopy and image processing have made it possible to solve the structure of alpha-synuclein fibrils at high resolution. This review discusses the results of structural studies using cryo-electron microscopy, which revealed that in-vitro produced fibrils vary in diameter from 5nm for single-protofilament fibrils, to 10nm for two-protofilament fibrils. In addition, the atomic models hint at contributions of the familial Parkinson's disease mutation sites to inter-protofilament interaction and the locations where post-translational modifications take place. Here, we propose a nomenclature system that allows identifying the existing alpha-synuclein polymorphs and that will allow to incorporate additional high-resolution structures determined in the future.

Topics: alpha-Synuclein; Cryoelectron Microscopy; Cytoskeleton; Humans; Mutation; Parkinson Disease

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the accumulation of α-synuclein (α-syn) into insoluble aggregates known as Lewy bodies and Lewy neurites in the brain. However, prior to the formation of these large aggregates, α-syn forms oligomers and small fibrils, which are believed to be the pathogenic species leading to the death of neurons in the substantia nigra in disease. The majority of aggregated α-syn is phosphorylated, and it is thought that this post-translational modification may be critical in disease pathogenesis. Thus, early detection of the toxic forms of α-syn may provide a window of opportunity for an intervention to halt or slow the progression of neurodegeneration in PD. Expression of α-syn is not restricted to the central nervous system and the protein can be found elsewhere, including bodily fluids and peripheral tissues. This review will examine current methods for detecting toxic forms of α-syn in accessible biospecimens and outline emerging techniques that may provide reliable identification of biomarkers for PD.

Topics: alpha-Synuclein; Animals; Biomarkers; Brain; Humans; Lewy Bodies; Parkinson Disease; Phosphorylation; Protein Aggregation, Pathological

The underline neuropathology of Parkinson disease is pleiomorphic and its genetic background diverse. Possibly because of this heterogeneity, no effective disease modifying therapy is available. In this paper we give an overview of the genetics of Parkinson disease and explain how this is relevant for the development of new therapies. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.

Topics: alpha-Synuclein; Animals; Anticonvulsants; Genetic Association Studies; Genetic Therapy; Humans; Immunotherapy; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Parkinson Disease

Parkinson's Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Parkinson Disease; Protein Aggregates

The two main pathological hallmarks of Parkinson's disease are loss of dopamine neurons in the substantia nigra pars compacta and proteinaceous amyloid fibrils composed mostly of α-synuclein, called Lewy pathology. Levodopa to enhance dopaminergic transmission remains one of the most effective treatment for alleviating the motor symptoms of Parkinson's disease (Olanow, Mov Disord 34:812-815, 2019). In addition, deep brain stimulation (Bronstein et al., Arch Neurol 68:165, 2011) to modulate basal ganglia circuit activity successfully alleviates some motor symptoms. MRI guided focused ultrasound in the subthalamic nucleus is a promising therapeutic strategy as well (Martinez-Fernandez et al., Lancet Neurol 17:54-63, 2018). However, to date, there exists no treatment that stops the progression of this disease. The findings that α-synuclein can be released from neurons and inherited through interconnected neural networks opened the door for discovering novel treatment strategies to prevent the formation and spread of Lewy pathology with the goal of halting PD in its tracks. This hypothesis is based on discoveries that pathologic aggregates of α-synuclein induce the endogenous α-synuclein protein to adopt a similar pathologic conformation, and is thus self-propagating. Phase I clinical trials are currently ongoing to test treatments such as immunotherapy to prevent the neuron to neuron spread of extracellular aggregates. Although tremendous progress has been made in understanding how Lewy pathology forms and spreads throughout the brain, cell intrinsic factors also play a critical role in the formation of pathologic α-synuclein, such as mechanisms that increase endogenous α-synuclein levels, selective expression profiles in distinct neuron subtypes, mutations and altered function of proteins involved in α-synuclein synthesis and degradation, and oxidative stress. Strategies that prevent the formation of pathologic α-synuclein should consider extracellular release and propagation, as well as neuron intrinsic mechanisms.

Topics: alpha-Synuclein; Animals; Brain; Disease Progression; Dopaminergic Neurons; Humans; Parkinson Disease; Protein Aggregates; Protein Aggregation, Pathological

Elucidating the structural details of proteins is highly valuable and important for the proper understanding of protein function. In the case of intrinsically disordered proteins (IDPs), however, obtaining the structural details is quite challenging, as the traditional structural biology tools have only limited use. Nuclear magnetic resonance (NMR) is a unique experimental tool that provides ensemble conformations of IDPs at atomic resolution, and when studying IDPs, a slightly different experimental strategy needs to be employed than the one used for globular proteins. We address this point by reviewing many NMR investigations carried out on the α-synuclein protein, the aggregation of which is strongly correlated with Parkinson's disease.

Topics: alpha-Synuclein; Humans; Nuclear Magnetic Resonance, Biomolecular; Parkinson Disease; Protein Aggregates; Protein Structure, Secondary

Aggregates of alpha-synuclein (αSyn) have been described in Parkinson's disease (PD) patients, and recent evidence has suggested that the most toxic αSyn species in PD are small soluble aggregates including oligomers, prefibrils, protofibrils. The physiological function of αSyn is still highly debated, with a possible role in synaptic vesicle trafficking and release at the presynaptic compartment, and in the regulation of gene expression in the nucleus. Emerging evidence indicate that most of αSyn functions are related with the crucial ability to bind biological membranes, which is associated with structural conversion from a disordered monomer to an α-helical enriched structure. Conformational properties of αSyn can be modulated by a number of factors including post-translational modifications, gene duplication and triplication-driven overexpression, single point mutations, environmental changes, which affect membrane binding and the protein propensity to aggregate in toxic species. The recognized toxic role of αSyn in PD has laid the rational for purposing of αSyn-based, neuropathologically relevant preclinical models of PD. Different approaches have led to the establishment of transgenic models, viral vector-based models, and more recently models based on the intracerebral inoculation of exogenous αSyn preformed fibrils/oligomers. Here, we overview and compare viral vector-based models of αSyn overexpression and models obtained by direct intracerebral infusion of in vitro preformed αSyn species. The advantages and pitfalls associated with these different approaches are discussed.

Topics: alpha-Synuclein; Animals; Humans; Parkinson Disease; Rodentia; Viruses

Most neurodegenerative diseases are characterized by the intracellular or extracellular aggregation of misfolded proteins such as amyloid-β and tau in Alzheimer disease, α-synuclein in Parkinson disease, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis. Accumulating evidence from both human studies and disease models indicates that intercellular transmission and the subsequent templated amplification of these misfolded proteins are involved in the onset and progression of various neurodegenerative diseases. The misfolded proteins that are transferred between cells are referred to as 'pathological seeds'. Recent studies have made exciting progress in identifying the characteristics of different pathological seeds, particularly those isolated from diseased brains. Advances have also been made in our understanding of the molecular mechanisms that regulate the transmission process, and the influence of the host cell on the conformation and properties of pathological seeds. The aim of this Review is to summarize our current knowledge of the cell-to-cell transmission of pathological proteins and to identify key questions for future investigation.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyotrophic Lateral Sclerosis; Axonal Transport; Brain; Cell Communication; DNA-Binding Proteins; Endocytosis; Exosomes; Genetic Predisposition to Disease; Humans; Huntingtin Protein; Huntington Disease; Membrane Fusion; Nanotubes; Neurodegenerative Diseases; Neuroglia; Neurons; Parkinson Disease; Protein Aggregation, Pathological; Protein Transport; tau Proteins

This study was aimed at investigating the effects and molecular mechanisms of physical activity intervention on Parkinson's disease (PD) and providing theoretical guidance for the prevention and treatment of PD.. Four electronic databases up to December 2019 were searched (PubMed, Springer, Elsevier, and Wiley database), 176 articles were selected. Literature data were analyzed by the logic analysis method.. (1) Risk factors of PD include dairy products, pesticides, traumatic brain injury, and obesity. Protective factors include alcohol, tobacco, coffee, black tea, and physical activity. (2) Physical activity can reduce the risk and improve symptoms of PD and the beneficial forms of physical activity, including running, dancing, traditional Chinese martial arts, yoga, and weight training. (3) Different forms of physical activity alleviate the symptoms of PD through different mechanisms, including reducing the accumulation of. Physical activity has a positive impact on the prevention and treatment of PD. Illustrating the molecular mechanism of physical activity-induced protective effect on PD is an urgent need for improving the efficacy of PD therapy regimens in the future.

Topics: alpha-Synuclein; Brain-Derived Neurotrophic Factor; Exercise; Exercise Therapy; Humans; Inflammation; Mitochondria; Oxidative Stress; Parkinson Disease; Risk Factors

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), increase as the population ages around the world. Environmental factors also play an important role in most cases. Alcohol consumption exists extensively and it acts as one of the environmental factors that promotes these neurodegenerative diseases. The brain is a major target for the actions of alcohol, and heavy alcohol consumption has long been associated with brain damage. Chronic alcohol intake leads to elevated glutamate-induced excitotoxicity, oxidative stress and permanent neuronal damage associated with malnutrition. The relationship and contributing mechanisms of alcohol with these three diseases are different. Epidemiological studies have reported a reduction in the prevalence of Alzheimer's disease in individuals who drink low amounts of alcohol; low or moderate concentrations of ethanol protect against β-amyloid (Aβ) toxicity in hippocampal neurons; and excessive amounts of ethanol increase accumulation of Aβ and Tau phosphorylation. Alcohol has been suggested to be either protective of, or not associated with, PD. However, experimental animal studies indicate that chronic heavy alcohol consumption may have dopamine neurotoxic effects through the induction of Cytochrome P450 2E1 (

Topics: Alcohol Drinking; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyotrophic Lateral Sclerosis; Animals; Brain; Cell Line; Disease Progression; Ethanol; Humans; Neurodegenerative Diseases; Neurons; Oxidative Stress; Parkinson Disease; Risk Factors

MicroRNAs (miRNAs) are small double-stranded RNAs that exert a fine-tuning sequence-specific regulation of cell transcriptome. While one unique miRNA regulates hundreds of mRNAs, each mRNA molecule is commonly regulated by various miRNAs that bind to complementary sequences at 3'-untranslated regions for triggering the mechanism of RNA interference. Unfortunately, dysregulated miRNAs play critical roles in many disorders, including Parkinson's disease (PD), the second most prevalent neurodegenerative disease in the world. Treatment of this slowly, progressive, and yet incurable pathology challenges neurologists. In addition to L-DOPA that restores dopaminergic transmission and ameliorate motor signs (i.e., bradykinesia, rigidity, tremors), patients commonly receive medication for mood disorders and autonomic dysfunctions. However, the effectiveness of L-DOPA declines over time, and the L-DOPA-induced dyskinesias commonly appear and become highly disabling. The discovery of more effective therapies capable of slowing disease progression -a neuroprotective agent-remains a critical need in PD. The present review focus on miRNAs as promising drug targets for PD, examining their role in underlying mechanisms of the disease, the strategies for controlling aberrant expressions, and, finally, the current technologies for translating these small molecules from bench to clinics.

Topics: alpha-Synuclein; Animals; Biotechnology; Humans; Inflammation; MicroRNAs; Parkinson Disease; Translational Research, Biomedical

Since the discovery of protein aggregates in the brains of individuals with Parkinson's disease (PD) in the early 20th century, the scientific community has been interested in the role of dysfunctional protein metabolism in PD etiology. Recent advances in the field have implicated defective protein handling underlying PD through genetic, in vitro, and in vivo studies incorporating many disease models alongside neuropathological evidence. Here, we discuss the existing body of research focused on understanding cellular pathways of protein synthesis and degradation, and how aberrations in either system could engender PD pathology with special attention to α-synuclein-related consequences. We consider transcription, translation, and post-translational modification to constitute protein synthesis, and protein degradation to encompass proteasome-, lysosome- and endoplasmic reticulum-dependent mechanisms. Novel findings connecting each of these steps in protein metabolism to development of PD indicate that deregulation of protein production and turnover remains an exciting area in PD research.

Topics: alpha-Synuclein; Animals; Autophagy; Humans; Parkinson Disease; Proteasome Endopeptidase Complex; Protein Biosynthesis; Proteolysis; Transcription, Genetic

In recent years, large-scale metagenomics projects such as the Human Microbiome Project placed the gut microbiota under the spotlight of research on its role in health and in the pathogenesis several diseases, as it can be a target for novel therapeutical approaches. The emerging concept of a microbiota modulation of the gut-brain axis in the pathogenesis of neurodegenerative disorders has been explored in several studies in animal models, as well as in human subjects. Particularly, research on changes in the composition of gut microbiota as a potential trigger for alpha-synuclein (α-syn) pathology in Parkinson's disease (PD) has gained increasing interest. In the present review, we first provide the basis to the understanding of the role of gut microbiota in healthy subjects and the molecular basis of the gut-brain interaction, focusing on metabolic and neuroinflammatory factors that could trigger the alpha-synuclein conformational changes and aggregation. Then, we critically explored preclinical and clinical studies reporting on the changes in gut microbiota in PD, as compared to healthy subjects. Furthermore, we examined the relationship between the gut microbiota and PD clinical features, discussing data consistently reported across studies, as well as the potential sources of inconsistencies. As a further step toward understanding the effects of gut microbiota on PD, we discussed the relationship between dysbiosis and response to dopamine replacement therapy, focusing on Levodopa metabolism. We conclude that further studies are needed to determine whether the gut microbiota changes observed so far in PD patients is the cause or, instead, it is merely a consequence of lifestyle changes associated with the disease. Regardless, studies so far strongly suggest that changes in microbiota appears to be impactful in pathogenesis of neuroinflammation. Thus, dysbiotic microbiota in PD could influence the disease course and response to medication, especially Levodopa. Future research will assess the impact of microbiota-directed therapeutic intervention in PD patients.

Topics: alpha-Synuclein; Animals; Dopamine Agents; Dysbiosis; Gastrointestinal Microbiome; Humans; Inflammation; Life Style; Parkinson Disease

The primary neuropathological characteristics of the Parkinsonian brain are the loss of nigral dopamine neurons and the aggregation of alpha synuclein protein. Efforts to development potentially disease-modifying treatments have largely focused on correcting these aspects of the condition. In the last decade treatments targeting protein aggregation have entered the clinical pipeline. In this chapter we provide an overview of ongoing clinical trial programs for different therapies attempting to reduce protein aggregation pathology in Parkinson's disease. We will also briefly consider various novel approaches being proposed-and being developed preclinically-to inhibit/reduce aggregated protein pathology in Parkinson's.

Topics: alpha-Synuclein; Animals; Humans; Immunologic Factors; Neuroprotective Agents; Parkinson Disease; Protein Aggregates; Vaccines

Parkinson's disease (PD) is the second most common neurodegenerative disease, disabling millions worldwide. Despite the imperative PD poses, at present, there is no cure or means of slowing progression. This gap is attributable to our incomplete understanding of the factors driving pathogenesis. Research over the past several decades suggests that both cell-autonomous and non-cell autonomous processes contribute to the neuronal dysfunction underlying PD symptoms. The thesis of this review is that an intersection of these processes governs the pattern of pathology in PD. Studies of substantia nigra pars compacta (SNc) dopaminergic neurons, whose loss is responsible for the core motor symptoms of PD, suggest that they have a combination of traits-a long, highly branched axon, autonomous activity, and elevated mitochondrial oxidant stress-that predispose them to non-cell autonomous drivers of pathogenesis, like misfolded forms of alpha-synuclein (α-SYN) and inflammation. The literature surrounding these issues will be briefly summarized, and the translational implications of an intersectional hypothesis of PD pathogenesis discussed.

Topics: alpha-Synuclein; Dopaminergic Neurons; Humans; Mitochondria; Parkinson Disease

Parkinson's Disease (PD) is a progressive neurodegenerative disorder with no cure. Clinical presentation is characterized by postural instability, resting tremors, and gait problems that result from progressive loss of A9 dopaminergic neurons in the substantia nigra pars compacta. Traumatic brain injury (TBI) has been implicated as a risk factor for several neurodegenerative diseases, but the strongest evidence is linked to development of PD. Mild TBI (mTBI), is the most common and is defined by minimal, if any, loss of consciousness and the absence of significant observable damage to the brain tissue. mTBI is responsible for a 56% higher risk of developing PD in U.S. Veterans and the risk increases with severity of injury. While the mounting evidence from human studies suggests a link between TBI and PD, fundamental questions as to whether TBI nucleates PD pathology or accelerates PD pathology in vulnerable populations remains unanswered. Several promising lines of research point to inflammation, metabolic dysregulation, and protein accumulation as potential mechanisms through which TBI can initiate or accelerate PD. Amyloid precursor protein (APP), alpha synuclein (α-syn), hyper-phosphorylated Tau, and TAR DNA-binding protein 43 (TDP-43), are some of the most frequently reported proteins upregulated following a TBI and are also closely linked to PD. Recently, upregulation of Leucine Rich Repeat Kinase 2 (LRRK2), has been found in the brain of mice following a TBI. Subset of Rab proteins were identified as biological substrates of LRRK2, a protein also extensively linked to late onset PD. Inhibition of LRRK2 was found to be neuroprotective in PD and TBI models. The goal of this review is to survey current literature concerning the mechanistic overlap between TBI and PD with a particular focus on inflammation, metabolic dysregulation, and aforementioned proteins. This review will also cover the application of rodent TBI models to further our understanding of the relationship between TBI and PD.

Topics: alpha-Synuclein; Amyloid beta-Protein Precursor; Animals; Blood-Brain Barrier; Brain Injuries, Traumatic; DNA-Binding Proteins; Energy Metabolism; Humans; Inflammation; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Parkinson Disease; Phosphorylation; Protein Aggregation, Pathological; rab GTP-Binding Proteins; Risk; tau Proteins; Up-Regulation

Proteinopathies are characterized by aging related accumulation of misfolded protein aggregates. Irreversible covalent modifications of aging proteins may significantly affect the native three dimentional conformation of proteins, alter their function and lead to accumulation of misfolded protein as dysfunctional aggregates. Protein misfolding and accumulation of aberrant proteins are known to be associated with aging-induced proteinopathies such as amyloid ß and tau proteins in Alzheimer's disease, α-synuclein in Parkinson's disease and islet amyloid polypeptides in Type 2 diabetes mellitus. Protein oxidation processes such as S-nitrosylation, dityrosine formation and some of the newly elucidated processes such as carbamylation and citrullination recently drew the attention of researchers in the field of Gerontology. Studying over these processes and illuminating their relations between proteinopathies may help to diagnose early and even to treat age related disorders. Therefore, we have chosen to concentrate on aging-induced proteinopathic nature of these novel protein modifications in this review.

Topics: Aging; alpha-Synuclein; Alzheimer Disease; Biomarkers; Diabetes Mellitus, Type 2; Humans; Islet Amyloid Polypeptide; Parkinson Disease; Proteostasis Deficiencies; tau Proteins

The proteostasis network controls the balance between protein synthesis, folding, function, and degradation, and ensures proteins are recycled when they are no longer needed or become damaged, avoiding unwanted aggregation and accumulation. In various neurological disorders, such as Parkinson's disease (PD) and other synucleinopathies, the accumulation of misfolded and aggregated alpha-synuclein (aSyn) is considered a central event in the onset and progression of disease. During aging, there is a decline in the activity of various degradation machineries, and the overall buffering capacity of the proteostasis network starts to decrease. Such decline is thought to play a pivotal role in PD, causing aSyn to build-up due to compromised clearance, which in turn contributes to further disease progression.In this chapter, we summarize central findings related to aSyn accumulation and degradation, as well as to the consequences of the toxic effects caused by aSyn on proteostasis. We also highlight some of the factors and pathways that may be used as potential targets for therapeutic interventions in PD.

Topics: alpha-Synuclein; Humans; Parkinson Disease; Proteostasis

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons and the accumulation of deposits of α-synuclein (α-syn) in the brain. The pivotal role of α-syn aggregation in PD makes it an attractive target for potential disease-modifying therapies. However, the disordered nature of the protein, its multistep aggregation mechanism, and the lack of structural information on intermediate species complicate the discovery of modulators of α-syn amyloid deposition. Despite these difficulties, small molecules have been shown to block the misfolding and aggregation of α-syn, and can even disentangle mature α-syn amyloid fibrils. In this review we provide an updated overview of these leading small compounds and discuss how these chemical chaperones hold great promise to alter the course of PD progression.

Topics: alpha-Synuclein; Amyloid; Humans; Molecular Chaperones; Parkinson Disease; Pharmaceutical Preparations; Small Molecule Libraries

Misfolding of the protein α-synuclein contributes to the formation of the intracellular inclusion, Lewy bodies. Although these structures are not exclusive to Parkinson's disease, nevertheless, their presence in the substantia nigra is mandatory for the pathological diagnosis of the disorder. Therefore, there must be a focus on the pathological mechanisms responsible for Lewy body generation. Recent studies have suggested that α-synuclein has the potential to operate as the enzyme ferrireductase. Perhaps in the early diseased state, overexpression or mutation of alpha-synuclein/ferrireductase invokes the dyshomeostasis of iron (III)/(II) only, while in advanced stages, accumulation of iron in particular areas of the brain follows. Furthermore, the loss of an important iron chelator, neuromelanin (due to dopaminergic neuronal death), may then result in the release and increase in unbound free iron. Iron could generate reactive oxygen species, which could instigate a torrent of cellular deleterious processes. In addition, loss of energy supply may contribute to the alteration in activity of enzymes involved in the mitochondrial respiratory chain and would, therefore, confer a vulnerability to the dopaminergic neurons in the substantia nigra. Therefore, the ferrireductase alpha-synuclein may hold the key for major pathology of Parkinson's disease. In conclusion, we hypothesize that environmentally or genetically overexpressed and/or mutated α-synuclein/ferrireductase causes iron dyshomeostasis without increase of free iron concentration in the early phases of PD, while increased iron concentration accompanied by iron dyshomeostasis is a marker for progressed PD stages. It is essential to elucidate these degenerative mechanisms, so as to provide effective therapeutic treatment to halt or delay the progression of the illness already in the early phase of PD. The development of iron chelators seems to be a reasonable approach.

Topics: alpha-Synuclein; FMN Reductase; Humans; Iron; Parkinson Disease

The lack of effective disease-modifying strategies is the major unmet clinical need in Parkinson´s disease. Several experimental approaches have attempted to validate cellular targets and processes. Of these, autophagy has received considerable attention in the last 20 years due to its involvement in the clearance of pathologic protein aggregates and maintenance of neuronal homeostasis. However, this strategy mainly addresses a very late stage of the disease, when neuropathology and neurodegeneration have likely "tipped over the edge" and disease modification is extremely difficult. Very recently, autophagy has been demonstrated to modulate synaptic activity, a process distinct from its catabolic function. Abnormalities in synaptic transmission are an early event in neurodegeneration with Leucine-Rich Repeat Kinase 2 (LRRK2) and alpha-synuclein strongly implicated. In this review, we analyzed these processes separately and then discussed the unification of these biomolecular fields with the aim of reconstructing a potential "molecular timeline" of disease onset and progression. We postulate that the elucidation of these pathogenic mechanisms will form a critical basis for the design of novel, effective disease-modifying therapies that could be applied early in the disease process.

Topics: alpha-Synuclein; Autophagy; Disease Progression; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Nerve Degeneration; Neurons; Parkinson Disease; Synapses

Parkinson's disease (PD) is the second most common neurodegenerative disease; it is characterized by the loss of dopaminergic neurons in the midbrain and the accumulation of neuronal inclusions, mainly consisting of α-synuclein (α-syn) fibrils in the affected regions. The prion-like property of the pathological forms of α-syn transmitted via neuronal circuits has been considered inherent in the nature of PD. Thus, one of the potential targets in terms of PD prevention is the suppression of α-syn conversion from the functional form to pathological forms. Recent studies suggested that α-syn interacts with synaptic vesicle membranes and modulate the synaptic functions. A series of studies suggest that transient interaction of α-syn as multimers with synaptic vesicle membranes composed of phospholipids and other lipids is required for its physiological function, while an α-syn-lipid interaction imbalance is believed to cause α-syn aggregation and the resultant pathological α-syn conversion. Altered lipid metabolisms have also been implicated in the modulation of PD pathogenesis. This review focuses on the current literature reporting the role of lipids, especially phospholipids, and lipid metabolism in α-syn dynamics and aggregation processes.

Topics: alpha-Synuclein; Animals; Humans; Lipid Metabolism; Parkinson Disease; Phospholipids; Synaptic Vesicles

Advances in the understanding of the mechanisms that lead to Lewy body pathology in Parkinson's disease (PD) have yielded rationales for tackling neurodegeneration associated with α-Synuclein (α-Syn) misfolding, aggregation, and/or its related spreading. Immunization therapies targeting distinct α-Syn epitopes (conformational and linear) that aim to limit extracellular spread in the brain are now in development. Completed and ongoing studies have enrolled early PD patients without considering individual clinical differences and assume a common pathogenetic mechanism of the disease. Such approaches have led to disappointing results; this is most likely attributed to trial methodology and inadequate patient selection rather than underlying target biology.. This review presents the status of immunotherapies that target α-Syn epitopes in PD. Mechanisms associated with neurodegeneration are examined along with the limitations of current antibody research strategies and ongoing clinical trials. Patient stratification based on disease progression is discussed and the article culminates with author suggestions on how to progress future clinical trials.. The efficacy of passive and active immunotherapies is inadequately evaluated in ongoing clinical trials where participating patients have various progression rates, genetic backgrounds, and clinical phenotypes. Future disease-modifying studies can overcome these limitations by enrolling patients based on progression pathways and genotypic contribution to disease manifestations.

Topics: alpha-Synuclein; Animals; Disease Progression; Humans; Immunization, Passive; Immunotherapy, Active; Parkinson Disease; Patient Selection

Neuronal homeostasis depends on both simple and complex sugars (the glycoconjugates), and derangement of their metabolism is liable to impair neural function and lead to neurodegeneration. Glucose levels boost glycation phenomena, a wide series of non-enzymatic reactions that give rise to various intermediates and end-products that are potentially dangerous in neurons. Glycoconjugates, including glycoproteins, glycolipids, and glycosaminoglycans, contribute to the constitution of the unique features of neuron membranes and extracellular matrix in the nervous system. Glycosylation defects are indeed frequently associated with nervous system disturbances and neurodegeneration. Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms associated with the loss of dopaminergic neurons in the pars compacta of the substantia nigra. Neurons present intracytoplasmic inclusions of α-synuclein aggregates involved in the disease pathogenesis together with the impairment of the autophagy-lysosome function, oxidative stress, and defective traffic and turnover of membrane components. In the present review, we selected relevant recent contributions concerning the direct involvement of glycation and glycosylation in α-synuclein stability, impaired autophagy and lysosomal function in PD, focusing on potential models of PD pathogenesis provided by genetic variants of glycosphingolipid processing enzymes, especially glucocerebrosidase (GBA). Moreover, we collected data aimed at defining the glycomic profile of PD patients as a tool to help in diagnosis and patient subtyping, as well as those pointing to sugar-related compounds with potential therapeutic applications in PD.

Topics: alpha-Synuclein; Animals; Autophagy; Dopaminergic Neurons; Glucose; Glycoconjugates; Humans; Inclusion Bodies; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders

The aggregation and deposition of α-synuclein (αS) are major pathologic features of Parkinson's disease, dementia with Lewy bodies, and other α-synucleinopathies. The propagation of αS pathology in the brain plays a key role in the onset and progression of clinical phenotypes. Thus, there is increasing interest in developing strategies that attenuate αS aggregation and propagation. Based on cumulative evidence that αS oligomers are neurotoxic and critical species in the pathogenesis of α-synucleinopathies, we and other groups reported that phenolic compounds inhibit αS aggregation including oligomerization, thereby ameliorating αS oligomer-induced cellular and synaptic toxicities. Heterogeneity in gut microbiota may influence the efficacy of dietary polyphenol metabolism. Our recent studies on the brain-penetrating polyphenolic acids 3-hydroxybenzoic acid (3-HBA), 3,4-dihydroxybenzoic acid (3,4-diHBA), and 3-hydroxyphenylacetic acid (3-HPPA), which are derived from gut microbiota-based metabolism of dietary polyphenols, demonstrated an in vitro ability to inhibit αS oligomerization and mediate aggregated αS-induced neurotoxicity. Additionally, 3-HPPA, 3,4-diHBA, 3-HBA, and 4-hydroxybenzoic acid significantly attenuated intracellular αS seeding aggregation in a cell-based system. This review focuses on recent research developments regarding neuroprotective properties, especially anti-αS aggregation effects, of phenolic compounds and their metabolites by the gut microbiome, including our findings in the pathogenesis of α-synucleinopathies.

Topics: alpha-Synuclein; Brain; Humans; Lewy Body Disease; Parkinson Disease; Phenols; Protein Aggregation, Pathological; Synucleinopathies

α-synuclein (SNCA), a major component of Lewy body is a pathological hallmark of Parkinson's disease (PD). Mutations in the SNCA gene cause misfolding and aggregation of SNCA protein, which results in neurodegeneration. Several studies have established the neuroprotective benefits of β2-adrenoreceptor (β2AR) agonists in PD However, β2AR agonists are associated with peripheral side effects- tachycardia, palpitation, pulmonary edema, myocardial ischemia, and cardiac arrhythmia due to βARactivation in peripheral tissues. PD therapy with β2AR agonists, therefore, warrants a brain-specific delivery.. This review highlights the SNCA mediated neurodegenerative pathways in PD and various treatment strategies under investigation to lower SNCA gene expression, primarily focusing on β2AR mediated pathway. The review also discusses the beneficial and side effects of β2AR agonists in PD treatment by reviewing clinical trials, epidemiological studies, and meta-analysis data. Here we depict the need to develop a novel drug delivery system to achieve brain-specific delivery of β2AR agonists to overcome peripheral side effects and also propose various nano delivery strategies to achieve the same.. Brain targeted delivery of β2AR agonists via various nano delivery systems will significantly downregulate SNCA gene expression in PD and also overcomes peripheral side effects of β2AR agonists.

Topics: Adrenergic beta-2 Receptor Agonists; alpha-Synuclein; Brain; Drug Delivery Systems; Gene Expression; Humans; Oxidative Stress; Parkinson Disease

Mitochondrial impairment is associated with progressive dopamine (DA) neuron degeneration in Parkinson's disease (PD). Recent findings highlight that Sirtuin-3 (SIRT3), a mitochondrial protein, is an oxidized nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase and a key modulator in maintaining integrity and functions of mitochondria. SIRT3 plays vital roles in regulation of mitochondrial functions, including mitochondrial ATP generation and energy metabolism, anti-oxidant defense, and cell death and proliferation. SIRT3 can deacetylate the transcriptional factors and crosstalk with different signaling pathways to cooperatively modulate mitochondrial functions and regulate defensive mitochondrial quality control (QC) systems. Down-regulated NAD+ level and decreased SIRT3 activity are related to aging process and has been pathologically linked to PD pathogenesis. Further, SIRT3 can bind and deacetylate PTEN-induced kinase 1 (PINK1) and PD protein 2 E3 ubiquitin protein ligase (Parkin) to facilitate mitophagy. Leucine Rich Repeat Kinase 2 (LRRK2)-G2019S mutation in PD is linked to SIRT3 impairment. Furthermore, SIRT3 is inversely associated with α-synuclein aggregation and DA neuron degeneration in PD. SIRT3 chemical activators and NAD+ precursors can up-regulate SIRT3 activity to protect against DA neuron degeneration in PD models. Taken together, SIRT3 is a promising PD therapeutic target and studies of SIRT3 functional modulators with neuroprotective capability will be of clinical interest.

Topics: alpha-Synuclein; Humans; Mitochondria; NAD; Parkinson Disease; Sirtuin 3

It was recently shown (Sampson et al., Elife9, 2020) that an amyloidogenic protein, CsgA, present in E. coli biofilms in the gut can trigger Parkinson's disease in mice. This study emphasizes the possible role of the gut microbiome in modulation (and even initiation) of human neurodegenerative disorders, such as Parkinson's disease. As the CsgA protein was found to accelerate alpha-synuclein (the key amyloidogenic protein in Parkinson's disease) amyloid formation in vitro, this result suggests that also other amyloidogenic proteins from gut bacteria, and even from the diet (such as stable allergenic proteins), may be able to affect human protein conformations and thereby modulate amyloid-related diseases. In this review, we summarize what has been reported in terms of in vitro cross-reactivity studies between alpha-synuclein and other amyloidogenic human and non-human proteins. It becomes clear from the limited data that exist that there is a fine line between acceleration and inhibition, but that cross-reactivity is widespread, and it is more common for other proteins (among the studied cases) to accelerate alpha-synuclein amyloid formation than to block it. It is of high importance to expand investigations of cross-reactivity between amyloidogenic proteins to both reveal underlying mechanisms and links between human diseases, as well as to develop new treatments that may be based on an altered gut microbiome.

Topics: alpha-Synuclein; Amyloid; Amyloidogenic Proteins; Animals; Humans; Neurodegenerative Diseases; Parkinson Disease; Protein Conformation

Amyloids are fibrous cross-β protein aggregates that are capable of proliferation via nucleated polymerization. Amyloid conformation likely represents an ancient protein fold and is linked to various biological or pathological manifestations. Self-perpetuating amyloid-based protein conformers provide a molecular basis for transmissible (infectious or heritable) protein isoforms, termed prions. Amyloids and prions, as well as other types of misfolded aggregated proteins are associated with a variety of devastating mammalian and human diseases, such as Alzheimer's, Parkinson's and Huntington's diseases, transmissible spongiform encephalopathies (TSEs), amyotrophic lateral sclerosis (ALS) and transthyretinopathies. In yeast and fungi, amyloid-based prions control phenotypically detectable heritable traits. Simplicity of cultivation requirements and availability of powerful genetic approaches makes yeast Saccharomyces cerevisiae an excellent model system for studying molecular and cellular mechanisms governing amyloid formation and propagation. Genetic techniques allowing for the expression of mammalian or human amyloidogenic and prionogenic proteins in yeast enable researchers to capitalize on yeast advantages for characterization of the properties of disease-related proteins. Chimeric constructs employing mammalian and human aggregation-prone proteins or domains, fused to fluorophores or to endogenous yeast proteins allow for cytological or phenotypic detection of disease-related protein aggregation in yeast cells. Yeast systems are amenable to high-throughput screening for antagonists of amyloid formation, propagation and/or toxicity. This review summarizes up to date achievements of yeast assays in application to studying mammalian and human disease-related aggregating proteins, and discusses both limitations and further perspectives of yeast-based strategies.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Amyotrophic Lateral Sclerosis; Animals; Humans; Parkinson Disease; Prion Diseases; Prions; Recombinant Fusion Proteins; Saccharomyces cerevisiae; tau Proteins

Mutations in the glucocerebrosidase (GBA1) gene are the most common genetic risk factor for Parkinson disease (PD). Homozygous or compound heterozygous GBA1 mutations cause the lysosomal storage disorder Gaucher disease (GD), characterized by deficient activity of the glucocerebrosidase enzyme (GCase). Both individuals with GD type I and heterozygous carriers of pathogenic variants of GBA1 have an increased risk of developing PD, by approximately ten- to 20-fold compared to non-carriers. GCase activity is also reduced in PD patients without GBA1 mutations, suggesting that the GCase lysosomal pathway might be involved in PD pathogenesis. Available evidence indicates that GCase can affect α-synuclein pathology in different ways. Misfolded GCase proteins are retained in the endoplasmic reticulum, altering the lysosomal trafficking of the enzyme and disrupting protein trafficking. Also, deficient GCase leads to accumulation of substrates that in turn may bind α-synuclein and promote pathological formation of aggregates. Furthermore, α-synuclein itself can lower the enzymatic activity of GCase, indicating that a bidirectional interaction exists between GCase and α-synuclein. Targeted therapies aimed at enhancing GCase activity, augmenting the trafficking of misfolded GCase proteins by small molecule chaperones, or reducing substrate accumulation, have been tested in preclinical and clinical trials. This article reviews the molecular mechanisms linking GCase to α-synuclein and discusses the therapeutic drugs that by targeting the GCase pathway can influence PD progression.

Topics: alpha-Synuclein; Animals; Disease Progression; Endoplasmic Reticulum; Genetic Predisposition to Disease; Glucosylceramidase; Humans; Mutation; Parkinson Disease; Protein Folding; Risk Factors

A vast advancement has been made in the treatment related to central nervous system disorders especially Parkinson's disease. The development in therapeutics and a better understanding of the targets results in upsurge of many promising therapies for Parkinson's disease. Parkinson's disease is defined by neuronal degeneration and neuroinflammation and it is reported that the presence of the neurofibrillary aggregates such as Lewy bodies is considered as the marker. Along with this, it is also characterized by the presence of motor and non-motor symptoms, as seen in Parkinsonian patients. A lot of treatment options mainly focus on prophylactic measures or the symptomatic treatment of Parkinson's disease. Neuroinflammation and neurodegeneration are the point of interest which can be exploited as a new target to emphasis on Parkinson's disease. A thorough study of these targets helps in modifications of those molecules which are particularly involved in causing the neuronal degeneration and neuroinflammation in Parkinson's disease. A lot of drug regimens are available for the treatment of Parkinson's disease, although levodopa remains the choice of drug for controlling the symptoms, yet is accompanied with significant snags. It is always suggested to use other drug therapies concomitantly with levodopa. A number of significant causes and therapeutic targets for Parkinson's disease have been identified in the last decade, here an attempt was made to highlight the most significant of them. It was also found that the treatment regimen and involvement of therapies are totally dependent on individuals and can be tailored to the needs of each individual patient.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Deep Brain Stimulation; Exercise Therapy; Humans; Inflammation Mediators; Lewy Bodies; Parkinson Disease; Treatment Outcome

Parkinson's disease (PD) is a disease of the human nervous system with an onset, in the sixth and seventh decades of the human life. Chiefly perceived as progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) with the ensued loss of dopamine in the striatum and the presence of Lewy bodies, consisting of α-synuclein agglomeration. In which the neuronal bridge between substantia nigra and striatum plays an advent role in the motor system. Dilapidation of these neurons results in dopamine depletion which in-turn makes hay to PD. Eventually, the etiology and pathogenesis of PD were still on a hike of dilemma. Traditional Chinese medicine (TCM), including Chinese herbal remedies, acupuncture, and manipulative therapies, is commonly used as an adjunctive therapy in different diseases, particularly neurological diseases, in Asian countries. Additionally, TCM might improve the prognoses and the quality of life of patients with PD because it induces less adverse drug reactions. The present review describes research on the various neuroprotective components and herbal extracts from herbal medicines in the context of addressing the effects of PD.

Topics: alpha-Synuclein; Animals; Brain; Corpus Striatum; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Humans; Medicine, Chinese Traditional; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Parkinson Disease; Pars Compacta; Substantia Nigra; Tyrosine 3-Monooxygenase

Parkinson's Disease (PD) is a neurological disease characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway with consequent loss of neurons in the substantia nigra pars compacta and dopamine depletion. The cytoplasmic inclusions of α-synuclein (α-Syn), known as Lewy bodies, are the cytologic hallmark of PD. The presence of α-Syn aggregates causes mitochondrial degeneration, responsible for the increase in oxidative stress and consequent neurodegeneration. PD is a progressive disease that shows a complicated pathogenesis. The current therapies are used to alleviate the symptoms of the disease without changing its clinical course. Recently, phytocompounds with neuroprotective effects and antioxidant properties such as caffeine have aroused the interest of researchers. The purpose of this review is to summarize the preclinical studies present in the literature and clinical trials recorded in ClinicalTrial.gov, aimed at illustrating the effects of caffeine used as a nutraceutical compound combined with the current PD therapies. Therefore, the preventive effects of caffeine in the neurodegeneration of dopaminergic neurons encourage the use of this alkaloid as a supplement to reduce the progress of the PD.

Topics: Alkaloids; alpha-Synuclein; Animals; Caffeine; Clinical Trials as Topic; Dopamine; Dopaminergic Neurons; Humans; Neuroprotective Agents; Parkinson Disease

The incidence of Parkinson's disease (PD) increases with age. PD is a neurodegenerative disease with an incidence of 1 in 200 individuals aged over 65 years. In patients with PD, α-synuclein may accumulate abnormally and damage cells in the substantia nigra. Abnormal proteins (α-synuclein) in peripheral tissues were recently found to be transferred to the brain rather than originating in the brain. Furthermore, changes in intestinal microbiota appear to be related to observed treatment effects and disease development in patients with PD. This review will report on recent studies of intestinal microbiota potentially involved in PD symptoms and progression.

Topics: Aged; alpha-Synuclein; Gastrointestinal Microbiome; Humans; Parkinson Disease; Substantia Nigra

Numerous single nucleotide polymorphisms (SNPs), which have been identified as susceptibility factors for Parkinson's disease (PD) as per genome-wide association studies, have not been fully characterized for PD patients in China. This study aimed to replicate the relationship between 12 novel SNPs of 12 genes and PD risk in southern Chinese population. Twelve SNPs of 12 genes were detected in 231 PD patients and 249 controls, using the SNaPshot technique. Meta-analysis was used to assess heterogeneity of effect sizes between this study and published data. The impact of SNPs on gene expression was investigated by analysing the SNP-gene association in the expression quantitative trait loci (eQTL) data sets. rs8180209 of SNCA (allele model: P = .047, OR = 0.77; additive model: P = .047, OR = 0.77), rs2270968 of MCCC1 (dominant model: P = .024, OR = 1.52), rs7479949 of DLG2 (recessive model; P = .019, OR = 1.52), rs10748818 of GBF1 (additive model: P < .001, OR = 0.37), and rs4771268 of MBNL2 (recessive model: P = .003, OR = 0.48) were replicated to be significantly associated with the increased risk of PD. Noteworthy, a meta-analysis of previous studies suggested rs8180209, rs2270968, rs7479949 and rs4771268 were in line with those of our cohort. Our study replicated five novel functional SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 could be associated with increased risk of PD in southern Chinese population.

Topics: Aged; Alleles; alpha-Synuclein; Carbon-Carbon Ligases; Case-Control Studies; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Guanine Nucleotide Exchange Factors; Guanylate Kinases; Humans; Male; Middle Aged; Odds Ratio; Parkinson Disease; Polymorphism, Single Nucleotide; Population Surveillance; RNA-Binding Proteins; Tumor Suppressor Proteins

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by motor system dysfunction. The etiology of PD has been linked with aging, environmental toxins and genetic mutation, while molecular pathogenesis of PD includes various factors, such as impaired protein homeostasis, oxidative stress, mitochondria dysfunction, synaptic transmission impairment, calcium homeostasis imbalance, prion-like α-synuclein transmission and neuron inflammation. Autophagy is a conserved bulk degradation process to maintain cellular homeostasis. Impairment of autophagy has been reported to be involved in the pathogenesis of PD. Coding proteins of several PD-related genes, such as SNCA, LRRK2, GBA, ATP13A2, VPS35 and FBXO7, are implicated in or affected by autophagy process. Furthermore, various pathogenic events during PD directly or indirectly interfere with the autophagy pathway, and dysregulation of autophagy has been observed in different neurotoxic PD models. Autophagy has been regarded as a potential therapeutic target for PD treatment. Indeed, modulations of autophagy-regulated genes (BECN1 and TFEB) expression exerted neuroprotection against PD models, and various autophagy regulators, such as rapamycin, trehalose, lysosome modulators and other small molecule autophagy inducers, have displayed neuroprotective effects in experimental PD models. Taken together, autophagy dysfunction has been implicated in the pathogenesis of PD, and pharmacological modulation of autophagy may be a new therapeutic strategy for the PD treatment.

Topics: alpha-Synuclein; Autophagy; Humans; Lysosomes; Parkinson Disease

The lysosome is a central player in the cell, acting as a clearing house for macromolecular degradation, but also plays a critical role in a variety of additional metabolic and regulatory processes. The lysosome has recently attracted the attention of neurobiologists and neurologists since a number of neurological diseases involve a lysosomal component. Among these is Parkinson's disease (PD). While heterozygous and homozygous mutations in

Topics: alpha-Synuclein; Animals; Brain; Glucosylceramidase; Humans; Lysosomal Storage Diseases; Lysosomes; Mutation; Parkinson Disease

The presence of intraneuronal Lewy bodies (LBs) and Lewy neurites (LNs) in the substantia nigra (SN) composed of aggregated α-synuclein (α-syn) has been recognized as a hallmark of pathological changes in Parkinson's disease (PD). Numerous studies have shown that aggregated α-syn is necessary for neurotoxicity. Meanwhile, the mitochondrial and lysosomal dysfunctions are associated with α-syn pathogenicity The hypothesis that α-syn transmission in the human brain contributes to the instigation and progression of PD has provided insights into PD pathology. This review will provide a brief overview of increasing researches that shed light on the relationship of α-syn aggregation with mitochondrial and lysosomal dysfunctions, and highlight recent understanding of α-syn transmission in PD pathology.

Topics: alpha-Synuclein; Animals; Cell Communication; Humans; Lewy Bodies; Lysosomes; Mitochondria; Neurons; Parkinson Disease; Protein Aggregation, Pathological

Mosaicism, the presence of genomic differences between cells due to post-zygotic somatic mutations, is widespread in the human body, including within the brain. A role for this in neurodegenerative diseases has long been hypothesised, and technical developments are now allowing the question to be addressed in detail. The rapidly accumulating evidence is discussed in this review, with a focus on recent developments. Somatic mutations of numerous types may occur, including single nucleotide variants (SNVs), copy number variants (CNVs), and retrotransposon insertions. They could act as initiators or risk factors, especially if they arise in development, although they could also result from the disease process, potentially contributing to progression. In common sporadic neurodegenerative disorders, relevant mutations have been reported in synucleinopathies, comprising somatic gains of SNCA in Parkinson's disease and multiple system atrophy, and in Alzheimer's disease, where a novel recombination mechanism leading to somatic variants of APP, as well as an excess of somatic SNVs affecting tau phosphorylation, have been reported. In Mendelian repeat expansion disorders, mosaicism due to somatic instability, first detected 25 years ago, has come to the forefront. Brain somatic SNVs occur in DNA repair disorders, and there is evidence for a role of several ALS genes in DNA repair. While numerous challenges, and need for further validation, remain, this new, or perhaps rediscovered, area of research has the potential to transform our understanding of neurodegeneration.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyotrophic Lateral Sclerosis; DNA Copy Number Variations; DNA Repair-Deficiency Disorders; DNA Repeat Expansion; Humans; Huntington Disease; Mosaicism; Multiple System Atrophy; Mutagenesis, Insertional; Mutation; Neurodegenerative Diseases; Parkinson Disease; Phosphorylation; Polymorphism, Single Nucleotide; Retroelements; Synucleinopathies; tau Proteins

While glia are essential for regulating the homeostasis in the normal brain, their dysfunction contributes to neurodegeneration in many brain diseases, including Parkinson's disease (PD). Recent studies have identified that PD-associated genes are expressed in glial cells as well as neurons and have crucial roles in microglia and astrocytes. Here, we discuss the role of microglia and astrocytes dysfunction in relation to PD-linked mutations and their implications in PD pathogenesis. A better understanding of microglia and astrocyte functions in PD may provide insights into neurodegeneration and novel therapeutic approaches for PD.

Topics: alpha-Synuclein; Astrocytes; Glucosylceramidase; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Microglia; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Ubiquitin-Protein Ligases

In Parkinson's disease (PD), neuronal alpha-synuclein aggregates are distributed throughout the nervous system, including the brain, spinal cord, sympathetic ganglia, submandibular gland, enteric nervous system, cardiac and pelvic plexuses, adrenal medulla, and skin. Thus, PD is a progressive multiorgan disease clinically associated with various motor and nonmotor symptoms. The earliest PD-related lesions appear to develop in the olfactory bulb, dorsal vagal nucleus, and possibly also the peripheral autonomic nervous system. The brain is closely connected with the enteric nervous system via axons of the efferent fibers of the dorsal nucleus of vagal nerve. Anatomical connections also exist between the olfactory bulb and brainstem. Accumulating evidence from experimental studies indicates that transneuronal propagation of misfolded alpha-synuclein is involved in the progression of PD. However, it cannot be ruled out that alpha-synuclein pathology in PD is multicentric in origin. Based on pathological findings from studies on human materials, the present review will update the progression pattern of alpha-synuclein pathology in PD.

Topics: alpha-Synuclein; Animals; Brain; Disease Progression; Humans; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting more than 10 million patients worldwide. Despite increasing improvements in disease management, a huge medical need still exists as its relentless progression cannot be delayed by current treatments. Therefore, scientists, clinicians, and pharmaceutical companies are hunting new drugs with 'disease-modifying' properties.. This review concentrates on new therapeutics - excluding cell and gene therapies - under investigation for PD with 'disease-modifying' potential. This is a global, comprehensive picture of the current innovative drug pipeline, where the main preclinical and clinical data available are provided. Drug candidates presented include α-synuclein modulating agents, neuroprotective agents and neuroinflammation modulators, kinase modulators, neurotrophic factors, and drugs acting on emerging targets.. There is excitement for agents with 'disease-modifying' properties and the authors found more than 130 assets, not including cell and gene therapies under investigation - most of them still in preclinical development - meaning that the science is progressing multiple, diverse new opportunities. Many limitations hamper the successful development of these drug candidates such as the translational accuracy of preclinical models, the current clinical development paradigm as well as the lack of biomarkers to be used in diagnosis and therapy management.

Topics: alpha-Synuclein; Cell- and Tissue-Based Therapy; Genetic Therapy; Humans; Immunologic Factors; Nerve Growth Factors; Neuroprotective Agents; Parkinson Disease; Phosphotransferases

Alzheimer's disease (AD), Parkinson's disease (PD), and depression are growing burdens for society globally, partly due to a lack of effective treatments. Mangosteen (

Topics: alpha-Synuclein; Alzheimer Disease; Amines; Amyloid beta-Peptides; Animals; Depression; Garcinia mangostana; Humans; Neurodegenerative Diseases; Parkinson Disease; Plant Extracts; Xanthones

Parkinson's disease (PD) is increasingly thought to be associated with glial pathology. Recently, research in neurodegenerative disorders has applied a greater focus to better understanding the role of astrocytes in the disease pathophysiology. In this article, we review results from the latest preclinical and clinical work, including functional imaging studies on astrocytes in PD and highlight key molecules that may prove valuable as biomarkers. We discuss how astrocytes may contribute to the initiation and progression of PD. We additionally present trials of investigational medicinal products and the current background for the design of future clinical trials.

Topics: Aging; alpha-Synuclein; Antioxidants; Astrocytes; Cholinergic Agonists; Disease Progression; Gliosis; Glutathione; Humans; Nerve Growth Factors; Nicotine; Parkinson Disease; Purinergic Antagonists; Risk Factors

Numerous lines of evidence indicate an association between sustained inflammation and Parkinson's disease, but whether increased inflammation is a cause or consequence of Parkinson's disease remains highly contested. Extensive efforts have been made to characterize microglial function in Parkinson's disease, but the role of peripheral immune cells is less understood. Natural killer cells are innate effector lymphocytes that primarily target and kill malignant cells. Recent scientific discoveries have unveiled numerous novel functions of natural killer cells, such as resolving inflammation, forming immunological memory, and modulating antigen-presenting cell function. Furthermore, natural killer cells are capable of homing to the central nervous system in neurological disorders that exhibit exacerbated inflammation and inhibit hyperactivated microglia. Recently, a study demonstrated that natural killer cells scavenge alpha-synuclein aggregates, the primary component of Lewy bodies, and systemic depletion of natural killer cells results in exacerbated neuropathology in a mouse model of alpha-synucleinopathy, making them a highly relevant cell type in Parkinson's disease. However, the exact role of natural killer cells in Parkinson's disease remains elusive. In this review, we introduce the systemic inflammatory process seen in Parkinson's disease, with a particular focus on the direct and indirect modulatory capacity of natural killer cells in the context of Parkinson's disease.

Topics: alpha-Synuclein; Animals; Cell Communication; Cellular Senescence; Cytokines; Disease Susceptibility; Gastrointestinal Tract; Humans; Immunity; Killer Cells, Natural; Neurons; Parkinson Disease; Receptors, Natural Killer Cell; Signal Transduction

Dementia is a rapidly rising global health crisis that silently disables families and ends lives and livelihoods around the world. To date, however, no early biomarkers or effective therapies exist. It is now clear that brain microglia are more than mere bystanders or amyloid phagocytes; they can act as governors of neuronal function and homeostasis in the adult brain. Here, we highlight the fundamental role of microglia as tissue-resident macrophages in neuronal health. Then, we suggest how chronic impairment in microglia-neuron cross-talk may secure the permanence of the failure of synaptic and neuronal function and health in Alzheimer's and Parkinson's diseases. Understanding how to assess and modulate microglia-neuron interactions critical for brain health will be key to developing effective therapies for dementia.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Animals; Cell Communication; Humans; Macrophages; Mice; Microglia; Neurons; Parkinson Disease; Synapses; Synaptosomes

Alpha-synuclein (α-Syn) is a 140-amino acid (aa) protein encoded by the Synuclein alpha SNCA gene. It is the synaptic protein associated with Parkinson's disease (PD) and is the most highly expressed protein in the Lewy bodies associated with PD and other alpha synucleopathies, including Lewy body dementia (LBD) and multiple system atrophy (MSA). Iron deposits are present in the core of Lewy bodies, and there are reports suggesting that divalent metal ions including Cu

Topics: 5' Untranslated Regions; Alcoholism; alpha-Synuclein; Brain; Gene Expression Regulation; Humans; Lewy Bodies; Neurons; Parkinson Disease; Small Molecule Libraries

The vast increase of world's aging populations is associated with increased risk of age-related neurodegenerative diseases such as Parkinson's disease (PD). PD is a widespread disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra, which encompasses a wide range of debilitating motor, emotional, cognitive, and physical symptoms. PD threatens the quality of life of millions of patients and their families. Additionally, public welfare and healthcare systems are burdened with its high cost of care. Available treatments provide only a symptomatic relief and produce a trail of noxious side effects, which increase noncompliance. Hence, researchers have recently focused on the use of nutraceuticals as safe adjunctive treatments of PD to limit its progress and associated damages in affected groups. Propolis is a common product of the beehive, which possesses a large number of therapeutic properties. Royal jelly (RJ) is a bee product that is fed to bee queens during their entire life, and it contributes to their high physical fitness, fertility, and long lifespan. Evidence suggests that propolis and RJ can promote health by preventing the occurrence of age-related debilitating diseases. Therefore, they have been used to treat various serious disorders such as diabetes mellitus, cardiovascular diseases, and cancer. Some evolving studies used these bee products to treat PD in animal models. However, a clear understanding of the collective effect of propolis and RJ as well as their mechanism of action in PD is lacking. This review evaluates the available literature for the effects of propolis and RJ on PD. Whenever possible, it elaborates on the underlying mechanisms through which they function in this disorder and offers insights for fruitful use of bee products in future clinical trials.

Topics: alpha-Synuclein; Animals; Apitherapy; Bees; Brain; Fatty Acids; Humans; Parkinson Disease; Propolis; Reactive Oxygen Species

α-Synuclein amyloid aggregation is a defining molecular feature of Parkinson's disease, Lewy body dementia, and multiple system atrophy, but can also be found in other neurodegenerative disorders such as Alzheimer's disease. The process of α-synuclein aggregation can be initiated through alternative nucleation mechanisms and dominated by different secondary processes giving rise to multiple amyloid polymorphs and intermediate species. Some aggregated species have more inherent abilities to induce cellular stress and toxicity, while others seem to be more potent in propagating neurodegeneration. The preference for particular types of polymorphs depends on the solution conditions and the cellular microenvironment that the protein encounters, which is likely related to the distinct cellular locations of α-synuclein inclusions in different synucleinopathies, and the existence of disease-specific amyloid polymorphs. In this review, we discuss our current understanding on the nature and structure of the various types of α-synuclein aggregated species and their possible roles in pathology. Precisely defining these distinct α-synuclein species will contribute to understanding the molecular origins of these disorders, developing accurate diagnoses, and designing effective therapeutic interventions for these highly debilitating neurodegenerative diseases.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Animals; Humans; Multiple System Atrophy; Parkinson Disease; Protein Aggregation, Pathological

Parkinson's disease (PD) is a common, age-related, neurodegenerative disorder characterized by motor deficits and a cognitive decline. In the large majority of cases, it is associated with cytoplasmic aggregation of α-synuclein/SNCA and the formation of Lewy bodies in the dopamine neurons in the substantia nigra pars compacta. The etiopathogenesis of PD remains poorly understood. The disease results from an interplay of genetic and environmental factors, including pharmacological molecules, which destroy dopaminergic neurons. Recently, several notable data have highlighted various immune alterations underlying that PD is associated to autoimmune features and could be considered as an autoimmune disease. In this short article, we briefly review key elements participating to this emerging viewpoint.

Topics: alpha-Synuclein; Autoimmune Diseases; Dopaminergic Neurons; Humans; Parkinson Disease

Lysosomal function has a central role in maintaining neuronal homeostasis, and, accordingly, lysosomal dysfunction has been linked to neurodegeneration and particularly to Parkinson's disease (PD). Lysosomes are the converging step where the substrates delivered by autophagy and endocytosis are degraded in order to recycle their primary components to rebuild new macromolecules. Genetic studies have revealed the important link between the lysosomal function and PD; several of the autosomal dominant and recessive genes associated with PD as well as several genetic risk factors encode for lysosomal, autophagic, and endosomal proteins. Mutations in these PD-associated genes can cause lysosomal dysfunction, and since α-synuclein degradation is mostly lysosomal-dependent, among other consequences, lysosomal impairment can affect α-synuclein turnover, contributing to increase its intracellular levels and therefore promoting its accumulation and aggregation. Recent studies have also highlighted the bidirectional link between Parkinson's disease and lysosomal storage diseases (LSD); evidence includes the presence of α-synuclein inclusions in the brain regions of patients with LSD and the identification of several lysosomal genes involved in LSD as genetic risk factors to develop PD.

Topics: alpha-Synuclein; Animals; Autophagy; Endosomes; Humans; Lysosomes; Neuroglia; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disorder, caused by, so far, unknown pathogenetic mechanisms. There is no doubt that pro-inflammatory immune-mediated mechanisms are pivotal to the pathogenicity and progression of the disease. In this review, we highlight the binary role of microglia activation in the pathophysiology of the disorder, both neuroprotective and neuromodulatory. We present how the expression of several cytokines implicated in dopaminergic neurons (DA) degeneration could be used as biomarkers for PD. Viral infections have been studied and correlated to the disease progression, usually operating as trigger factors for the inflammatory process. The gut-brain axis and the possible contribution of the peripheral bowel inflammation to neuronal death, mainly dopaminergic neurons, seems to be a main contributor of brain neuroinflammation. The role of the immune system has also been analyzed implicating a-synuclein in the activation of innate and adaptive immunity. We also discuss therapeutic approaches concerning PD and neuroinflammation, which have been studied in experimental and in vitro models and data stemming from epidemiological studies.

Topics: alpha-Synuclein; Animals; Autoimmunity; Biomarkers; Cytokines; Dopaminergic Neurons; Humans; Inflammation; Microglia; Nerve Degeneration; Parkinson Disease; Parkinsonian Disorders; Signal Transduction; Virus Diseases

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by neuronal loss and dysfunction of dopaminergic neurons located in the substantia nigra, which contain a variety of misfolded α-synuclein (α-syn). Medications that increase or substitute for dopamine can be used for the treatment of PD. Recently, numerous studies have shown gut microbiota plays a crucial role in regulating and maintaining multiple aspects of host physiology including host metabolism and neurodevelopment. In this review article, the role of gut microbiota in the etiological mechanism of PD will be reviewed. Furthermore, we discussed current pharmaceutical medicine-based methods to prevent and treat PD, followed by describing specific strains that affect the host brain function through the gut-brain axis. We explained in detail how gut microbiota directly produces neurotransmitters or regulate the host biosynthesis of neurotransmitters. The neurotransmitters secreted by the intestinal lumen bacteria may induce epithelial cells to release molecules that, in turn, can regulate neural signaling in the enteric nervous system and subsequently control brain function and behavior through the brain-gut axis. Finally, we proved that the microbial regulation of the host neuronal system. Endogenous α-syn can be transmitted long distance and bidirectional between ENS and brain through the circulatory system which gives us a new option that the possibility of altering the community of gut microbiota in completely new medication option for treating PD.

Topics: alpha-Synuclein; Brain; Enteric Nervous System; Gastrointestinal Microbiome; Humans; Parkinson Disease

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Creutzfeldt-Jakob disease (CJD) are brain conditions affecting millions of people worldwide. These diseases are associated with the presence of amyloid-β (Aβ), alpha synuclein (α-Syn) and prion protein (PrP) depositions in the brain, respectively, which lead to synaptic disconnection and subsequent progressive neuronal death. Although considerable progress has been made in elucidating the pathogenesis of these diseases, the specific mechanisms of their origins remain largely unknown. A body of research suggests a potential association between host microbiota, neuroinflammation and dementia, either directly due to bacterial brain invasion because of barrier leakage and production of toxins and inflammation, or indirectly by modulating the immune response. In the present review, we focus on the emerging topics of neuroinflammation and the association between components of the human microbiota and the deposition of Aβ, α-Syn and PrP in the brain. Special focus is given to gut and oral bacteria and biofilms and to the potential mechanisms associating microbiome dysbiosis and toxin production with neurodegeneration. The roles of neuroinflammation, protein misfolding and cellular mediators in membrane damage and increased permeability are also discussed.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain; Humans; Microbiota; Parkinson Disease

α-synuclein (α-syn) is a protein associated with the pathogenesis of Parkinson's disease (PD), the second most common neurodegeneration disease with no effective treatment. However, how α-syn drives the pathology of PD remains elusive. Recent studies suggest that α-syn oligomers are the primary cause of neurotoxicity and play a critical role in PD. In this review, we discuss the process of α-syn oligomers formation and the current understanding of the structures of oligomers. We also describe seed and propagation effects of oligomeric forms of α-syn. Then, we summarize the mechanism by which α-syn oligomers exert neurotoxicity and promote neurodegeneration, including mitochondrial dysfunction, endoplasmic reticulum stress, proteostasis dysregulation, synaptic impairment, cell apoptosis and neuroinflammation. Finally, we investigate treatment regimens targeting α-syn oligomers at present. Further research is needed to understand the structure and toxicity mechanism of different types of oligomers, so as to provide theoretical basis for the treatment of PD.

Topics: alpha-Synuclein; Animals; Apoptosis; Endoplasmic Reticulum Stress; Humans; Inflammation; Mitochondria; Parkinson Disease; Protein Multimerization; Proteostasis

The primary pathogenesis associated with Parkinson's disease (PD) occurs in peripheral tissues several years before the onset of typical motor symptoms. Early and reliable diagnosis of PD could provide new treatment options for PD patients and improve their quality of life. At present, however, diagnosis relies mainly on clinical symptoms, and definitive diagnosis is still based on postmortem pathological confirmation of dopaminergic neuronal degeneration. In addition, the similarity of the clinical, cognitive, and neuropathological features of PD with other neurodegenerative diseases calls for new biomarkers, suitable for differential diagnosis. Alpha-synuclein (α-Syn) is a potential PD biomarker, due to its close connection with the pathogenesis of the disease. Here we summarize the currently available information on the possible use of α-Syn as a biomarker of early stages of PD in gastrointestinal (GI) tissues, highlight its potential to distinguish PD and other neurodegenerative diseases, and suggest alternative methods (primarily developed for other tissue analysis) that could improve α-Syn detection procedures or diagnostic methods in general.

Topics: alpha-Synuclein; Biomarkers; Diagnosis, Differential; Early Diagnosis; Gastrointestinal Tract; Humans; Parkinson Disease

Parkinson's disease (PD) is diagnosed when patients exhibit bradykinesia with tremor and/or rigidity, and when these symptoms respond to dopaminergic medications. Yet in the last years there was a greater recognition of additional aspects of the disease including non-motor symptoms and prodromal states with associated pathology in various regions of the nervous system. In this review we discuss current concepts of two major alterations found during the course of the disease: cytoplasmic aggregates of the protein α-synuclein and the degeneration of dopaminergic neurons. We provide an overview of new approaches in this field based on current concepts and latest literature. In many areas, translational research on PD has advanced the understanding of the disease but there is still a need for more effective therapeutic options based on the insights into the basic biological phenomena.

Topics: alpha-Synuclein; Dopamine; Dopaminergic Neurons; Humans; Parkinson Disease; Prodromal Symptoms; Translational Research, Biomedical

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are common genetic risk factors for both familial and sporadic Parkinson's disease (PD). Pathogenic mutations in LRRK2 have been shown to induce changes in its activity, and abnormal increase in LRRK2 kinase activity is thought to contribute to PD pathology. The precise molecular mechanisms underlying LRRK2-associated PD pathology are far from clear, however the identification of LRRK2 substrates and the elucidation of cellular pathways involved suggest a role of LRRK2 in microtubule dynamics, vesicular trafficking, and synaptic transmission. Moreover, LRRK2 is associated with pathologies of α-synuclein, a major component of Lewy bodies (LBs). Evidence from various cellular and animal models supports a role of LRRK2 in the regulation of aggregation and propagation of α-synuclein. Here, we summarize our current understanding of how pathogenic mutations dysregulate LRRK2 and discuss the possible mechanisms leading to neurodegeneration.

Topics: alpha-Synuclein; Animals; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease; Signal Transduction

Over recent years, several investigations have suggested that Parkinson's disease (PD) can be regarded as the consequence of a bowel disorder. Indeed, gastrointestinal symptoms can occur at all stages of this neurodegenerative disease and in up to a third of cases, their onset can precede the involvement of the central nervous system. Recent data suggest that enteric glial cells (EGCs) may play a major role in PD-related gastrointestinal disturbances, as well as in the development and progression of the central disease. In addition to their trophic and structural functions, EGCs are crucial for the homeostatic control of a wide range of gastrointestinal activities. The main purpose of this review was to provide a detailed overview of the role of EGCs in intestinal PD-associated alterations, with particular regard for their participation in digestive and central inflammation as well as the dynamic interactions between glial cells and intestinal epithelial barrier. Accumulating evidence suggests that several pathological intestinal conditions, associated with an impairment of barrier permeability, may trigger dysfunctions of EGCs and their shift towards a proinflammatory phenotype. The reactive gliosis is likely responsible for PD-related neuroinflammation and the associated pathological changes in the ENS. Thus, ameliorating the efficiency of mucosal barrier, as well as avoiding IEB disruption and the related reactive gliosis, might theoretically prevent the onset of PD or, at least, counteract its progression.

Topics: alpha-Synuclein; Animals; Brain; Enteric Nervous System; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Neuroglia; Parkinson Disease; Signal Transduction

Parkinson's disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.

Topics: alpha-Synuclein; Animals; Antioxidants; Astrocytes; Disease Progression; Dopamine; Dopaminergic Neurons; Humans; Inflammation; Mitochondria; Nerve Degeneration; Neuroglia; Neurons; Neuroprotection; Oxidative Stress; Parkinson Disease; Signal Transduction

Neuronal lesions in Parkinson's disease (PD) are commonly associated with α-synuclein (α-Syn)-induced cell damage that are present both in the central and peripheral nervous systems of patients, with the enteric nervous system also being especially vulnerable. Here, we bring together evidence that the development and presence of PD depends on specific sets of interlinking factors that include neuroinflammation, systemic inflammation, α-Syn-induced cell damage, vascular dysfunction, iron dysregulation, and gut and periodontal dysbiosis. We argue that there is significant evidence that bacterial inflammagens fuel this systemic inflammation, and might be central to the development of PD. We also discuss the processes whereby bacterial inflammagens may be involved in causing nucleation of proteins, including of α-Syn. Lastly, we review evidence that iron chelation, pre-and probiotics, as well as antibiotics and faecal transplant treatment might be valuable treatments in PD. A most important consideration, however, is that these therapeutic options need to be validated and tested in randomized controlled clinical trials. However, targeting underlying mechanisms of PD, including gut dysbiosis and iron toxicity, have potentially opened up possibilities of a wide variety of novel treatments, which may relieve the characteristic motor and nonmotor deficits of PD, and may even slow the progression and/or accompanying gut-related conditions of the disease.

Topics: alpha-Synuclein; Animals; Dysbiosis; Gastrointestinal Microbiome; Humans; Inflammation; Iron; Mouth; Oxidative Stress; Parkinson Disease

Parkinson's disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disease. α-Synuclein (α-syn), which is the main protein component of Lewy bodies, plays an important role in the pathological hallmarks of PD. However, the pathological function of α-syn and the molecular mechanisms responsible for the degeneration of dopaminergic neurons are still elusive.. Cumulative evidence implicates that abnormal processing of α-syn will be predicted to lead to pathological changes in PD. Key Messages: In this review, we summarize the structure and physiological function of α-syn, and further discuss the interplay of pathology, neuroinflammation, and environmental factors in PD. Additionally, we suggest future directions for understanding the toxicity of α-syn to neurons, which may ultimately encourage us to better design disease-modifying therapeutic strategies for PD.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Humans; Parkinson Disease

The aberrant aggregation of normally soluble proteins into amyloid fibrils is the pathological hallmark of several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Understanding this process will be key to developing both diagnostic and therapeutic approaches for neurodegenerative diseases. Recent advances in biophysical techniques, coupled with kinetic analyses have enabled a thorough description of the key molecular steps involved in protein aggregation. In this review, we discuss these advances and how they have been applied to study the ability of one such protein, α-Synuclein, to form neurotoxic oligomers.

Topics: alpha-Synuclein; Humans; Parkinson Disease; Protein Aggregation, Pathological; Protein Binding

Recently, there has been a surge in awareness of the gastrointestinal microbiome (GM) and its role in health and disease. Of particular note is an association between the GM and Parkinson's disease (PD) and the realisation that the GM can act via a complex bidirectional communication between the gut and the brain. Compelling evidence suggests that a shift in GM composition may play an important role in the pathogenesis of PD by facilitating the characteristic ascending neurodegenerative spread of α-synuclein aggregates from the enteric nervous system to the brain. Here, we review evidence linking GM changes with PD, highlighting mechanisms supportive of pathological α-synuclein spread and intestinal inflammation in PD. We summarise existing patterns and correlations seen in clinical studies of the GM in PD, together with the impacts of non-motor symptoms, medications, lifestyle, diet and ageing on the GM. Roles of GM modulating therapies including probiotics and faecal microbiota transplantation are discussed. Encouragingly, alterations in the GM have repeatedly been observed in PD, supporting a biological link and highlighting it as a potential therapeutic target.

Topics: alpha-Synuclein; Enteric Nervous System; Gastrointestinal Microbiome; Humans; Inflammation; Parkinson Disease

The search for a reliable, early-disease biomarker for Parkinson's disease (PD) that reflects underlying pathology is a high priority in PD research. Salivary alpha-synuclein (α-Syn) is an easily accessible biomarker for PD with promising results. Our aim was to evaluate the performance of salivary α-Syn as a diagnostic biomarker of PD. We identified 476 studies through a systematic literature review according to PRISMA guidelines. Finally, eight studies reporting data on salivary α-Syn were included in the review (1240 participants). The quality of studies was assessed by Newcastle-Ottawa scale. (1) Three studies showed that the total α-Syn levels were significantly lower in PD patients compared to healthy controls, while in another five there was no significant association. (2) In some studies, total salivary α-Syn was associated with demographic and clinical features; however, no consistent pattern emerged. In one study, total α-Syn levels were associated with poor cognitive performance in PD patients. (3) Four studies showed a higher salivary oligomeric α-Syn and oligomeric α-Syn/total α-Syn ratio in PD compared to healthy controls, while in another four there was no association. (4) One study concluded that genetic polymorphisms may influence total salivary α-Syn in PD patients. Taken together, the potential of salivary total α-Syn as a PD biomarker is still uncertain, whereas salivary oligomeric α-Syn appears quite promising. Pre-analytical and analytical factors of included studies were important limitations to justify the introduction of salivary α-Syn into clinical practice.

Topics: alpha-Synuclein; Biomarkers; Humans; Parkinson Disease; Saliva

Neurodegenerative diseases, such as Parkinson's and Alzheimer's, affect millions of people and pose major personal and socioeconomic burdens. The causes of neurodegeneration are mostly unknown, although current efforts have described an autoimmune aspect to these diseases. Here we discuss recent findings that shed light on the involvement of the adaptive immune system in Parkinson's and Alzheimer's diseases, and provide a model and outlook for further investigation of T cell responses in neurodegenerative disease. We focus on the identification of T cell epitopes from proteins involved in disease pathogenesis and describe the identification of α-synuclein-specific epitopes in Parkinson's disease which provided a crucial link between disease susceptibility and T cell recognition.

Topics: Adaptive Immunity; alpha-Synuclein; Alzheimer Disease; Animals; Autoimmunity; Disease Susceptibility; Epitopes, T-Lymphocyte; Humans; Parkinson Disease; T-Lymphocytes

Parkinson's disease (PD) patients have higher rates of melanoma and vice versa, observations suggesting that the two conditions may share common pathogenic pathways. β-Catenin is a transcriptional cofactor that, when concentrated in the nucleus, upregulates the expression of canonical Wnt target genes, such as Nurr1, many of which are important for neuronal survival. β-Catenin-mediated activity is decreased in sporadic PD as well as in leucine-rich repeat kinase 2 (LRRK2) and β-glucosidase (GBA) mutation cellular models of PD, which is the most common genetic cause of and risk for PD, respectively. In addition, β-catenin expression is significantly decreased in more aggressive and metastatic melanoma. Multiple observational studies have shown smokers to have significantly lower rates of PD as well as melanoma implying that tobacco may contain one or more elements that protect against both conditions. In support, smoker's brains have significantly reduced levels of α-synuclein, a pathological intracellular protein found in PD brain and melanoma cells. Tobacco contains very high lithium levels compared to other plants. Lithium has a broad array of neuroprotective actions, including enhancing autophagy and reducing intracellular α-synuclein levels, and is effective in both neurotoxin and transgenic preclinical PD models. One of lithium's neuroprotective actions is enhancement of β-catenin-mediated activity leading to increased Nurr1 expression through its ability to inhibit glycogen synthase kinase-3 β (GSK-3β). Lithium also has anti-proliferative effects on melanoma cells and the clinical use of lithium is associated with a reduced incidence of melanoma as well as reduced melanoma-associated mortality. This is the first known report hypothesizing that inhaled lithium from smoking may account for the associated reduced rates of both PD and melanoma and that this protection may be mediated, in part, through lithium-induced GSK-3β inhibition and consequent enhanced β-catenin-mediated activity. This hypothesis could be directly tested in clinical trials assessing lithium therapy's ability to affect β-catenin-mediated activity and slow disease progression in patients with PD or melanoma.

Topics: alpha-Synuclein; Alzheimer Disease; Autophagy; beta Catenin; beta-Glucosidase; Brain Chemistry; Drug Evaluation, Preclinical; Glycogen Synthase Kinase 3 beta; Humans; Incidence; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lithium; Lithium Carbonate; Melanoma; Models, Biological; Mutation; Neuroprotective Agents; Nicotiana; Nuclear Receptor Subfamily 4, Group A, Member 2; Parkinson Disease; Parkinsonian Disorders; Smokers; Water; Wnt Signaling Pathway

The key molecular events that provoke Parkinson's disease (PD) are not fully understood. Iron deposit was found in the substantia nigra pars compacta (SNpc) of PD patients and animal models, where dopaminergic neurons degeneration occurred selectively. The mechanisms involved in disturbed iron metabolism remain unknown, however, considerable evidence indicates that iron transporters dysregulation, activation of L-type voltage-gated calcium channel (LTCC) and ATP-sensitive potassium (KATP) channels, as well as N-methyl-D-aspartate (NMDA) receptors (NMDARs) contribute to this process. There is emerging evidence on the structural links and functional modulations between iron and α-synuclein, and the key player in PD which aggregates in Lewy bodies. Iron is believed to modulate α-synuclein synthesis, post-translational modification, and aggregation. Furthermore, glia, especially activated astroglia and microglia, are involved in iron deposit in PD. Glial contributions were largely dependent on the factors they released, e.g., neurotrophic factors, pro-inflammatory factors, lactoferrin, and those undetermined. Therefore, iron chelation using iron chelators, the extracts from many natural foods with iron chelating properties, may be an effective therapy for prevention and treatment of the disease.

Topics: alpha-Synuclein; Animals; Calcium Channels, L-Type; Dopaminergic Neurons; Humans; Iron; KATP Channels; Parkinson Disease; Receptors, N-Methyl-D-Aspartate; Substantia Nigra

Parkinson's disease (PD) is a highly heterogeneous disorder, which probably consists of multiple subtypes. Aggregation of misfolded alpha-synuclein and propagation of these proteinacious aggregates through interconnected neural networks is believed to be a crucial pathogenetic factor. It has been hypothesized that the initial pathological alpha-synuclein aggregates originate in the enteric or peripheral nervous system (PNS) and invade the central nervous system (CNS) via retrograde vagal transport. However, evidence from neuropathological studies suggests that not all PD patients can be reconciled with this hypothesis. Importantly, a small fraction of patients do not show pathology in the dorsal motor nucleus of the vagus. Here, it is hypothesized that PD can be divided into a PNS-first and a CNS-first subtype. The former is tightly associated with REM sleep behavior disorder (RBD) during the prodromal phase and is characterized by marked autonomic damage before involvement of the dopaminergic system. In contrast, the CNS-first phenotype is most often RBD-negative during the prodromal phase and characterized by nigrostriatal dopaminergic dysfunction prior to involvement of the autonomic PNS. The existence of these subtypes is supported by in vivo imaging studies of RBD-positive and RBD-negative patient groups and by histological evidence- reviewed herein. The present proposal provides a fresh hypothesis-generating framework for future studies into the etiopathogenesis of PD and seems capable of explaining a number of discrepant findings in the neuropathological literature.

Topics: alpha-Synuclein; Autonomic Nervous System; Central Nervous System; Dopamine; Humans; Parkinson Disease; Prodromal Symptoms

Microglia are the most abundant immune cells in the central nervous system (CNS), where they interact with neurons and exhibit a wide array of functions in physiological and pathological conditions. Physiologically, microglia mediate synaptic pruning and remodeling crucial for neural circuits and brain connectivity. In pathological conditions such as neurodegeneration in the Parkinson's disease (PD), microglia are activated, migrated to the injury site, and prone to engulf debris, sense pathology, and secrete possible pro- and anti-inflammatory factors. Microglia mediate responses such as inflammation and phagocytosis associated with neurodegeneration and are pivotal players in exacerbating or relieving disease progression. This chapter provides an overview on microglial function in the neurodegenerative disease-Parkinson's disease (PD). An overview on the pathology of PD will first be given, followed by discussion on receptors and signaling pathways involved in microglia-mediated inflammation and phagocytosis. Mechanism of how microglia contribute to PD by inflammation, phagocytosis of α-Synuclein (α-Syn), and interaction with PD genes will also be discussed.

Topics: alpha-Synuclein; Humans; Inflammation; Microglia; Parkinson Disease; Phagocytosis; Signal Transduction

Parkin and alpha-synuclein (α-syn) are two key proteins involved in the pathophysiology of Parkinson's disease (PD). Oligomerization/aggregation and excessive secretion of α-syn contributes to PD through free radical stress, mitochondrial impairment, and synaptic dysfunction. Parkin, an E3 ubiquitin ligase, is considered to be a pleiotropic, neuroprotective protein that modulates metabolic turnover and the accumulation of α-syn. This is in addition to parkin's role in counteracting the more distant effects of α-syn on cellular survival by altering proteasomal, autophagic, and calpain-mediated protein degradation pathways that can reduce α-syn levels. Moreover, parkin regulates mitochondrial turnover, cell survival, and immune phenomena - processes that are all known to be disturbed in PD. In addition, parkin might have an impact on the spreading and propagation of α-syn by controlling its post-translational modifications. On the other hand, recent research has shown that α-syn oligomers affect the expression, post-translational modification, and activity of parkin. This review focuses on the molecular mechanisms of cross-talk between parkin and α-syn in PD. The physical and functional interactions between α-syn and parkin, which have been incompletely characterized to-date, may present a new therapeutic avenue in PD and related synucleinopathies. The development of effective, clinically feasible modulators may offer great hopes for the the rapy of PD.

Topics: alpha-Synuclein; Animals; Brain; Humans; Mutation; Parkinson Disease; Phosphorylation; Ubiquitin-Protein Ligases

The gastrointestinal (GI) tract is equipped with robust immune defenses which protect the organism from infection. Enteric nerves are front and center in this defensive network, even in the most primitive organisms. Neuropeptides exhibit potent antimicrobial activity in the vicinity of the nerve and attract the innate and adaptive immune systems to help confine the invading agent. Alpha-synuclein (αS) has many biophysical characteristics of antimicrobial peptides and binds small vesicles such as those carrying endocytosed viruses. It is induced in nerve cells in response to viral and bacterial infections. It renders the nerve cell resistant to viral infection and propagation. It signals the immune system by attracting neutrophils and macrophages, and by activating dendritic cells. Most remarkably αS is trafficked to the central nervous system (CNS) conferring immunity in advance of an infection. Chronic GI infection or breakdown of the epithelial barrier can cause αS to accumulate and form neurotoxic aggregates. Overproduction of αS in the enteric nervous system (ENS) and its chronic trafficking to the CNS may damage nerves and lead to Parkinson's disease. Targeting the formation of αS aggregates in the ENS may therefore slow the progression of the disease.

Topics: alpha-Synuclein; Animals; Antimicrobial Cationic Peptides; Enteric Nervous System; Humans; Immunity; Neuropeptides; Parkinson Disease

Parkinson's disease (PD) devastates 6.3 million people, ranking it as one of the most prevalent neurodegenerative motor disorders worldwide. PD patients may manifest symptoms of postural instability, bradykinesia, and resting tremors as a result of increasing α-synuclein aggregation and neuron death with disease progression. Therapy options are limited, and those available to patients may worsen their condition. Thus, investigations to understand disease progression may help develop therapeutic strategies for improvement of quality of life for patients suffering from PD. This review provides an overview of α-synuclein, a presynaptic neuronal protein whose function in the healthy brain and PD pathology remains a mystery. This review also focuses on calcium-induced activation of calpain, a neutral protease, and the subsequent cascade of cellular processing of α-synuclein and emerging defense responses observed in experimental models of PD: microglial activation, dysregulation of T cells, and inflammatory responses in the brain. In addition, this review discusses the events of cross presentation of synuclein peptides by professional antigen presenting cells and microglia, induction of inflammatory responses in the periphery and brain, and emerging calpain-targeted therapeutic strategies to attenuate neuronal death in PD.

Topics: alpha-Synuclein; Animals; Calpain; Humans; Inflammation; Microglia; Parkinson Disease

Parkinson's disease (PD) has long been considered a brain disease, but studies now point to the gastrointestinal (GI) tract as a potential starting point for PD. In particular, the human vermiform appendix has been implicated in PD. The appendix is a tissue rich in immune cells, serving as part of the gut-associated lymphoid tissue and as a storehouse for the gut microbiome. The functions of the appendix converge with recent evidence demonstrating that gut inflammation and shifts in the microbiome are linked to PD. Some epidemiological studies have linked removal of the appendix to lowered PD risk, though there is controversy among these associations. What is apparent is that there is an abundance of aggregated forms of α-synuclein in the appendix relevant to PD pathology. α-Synuclein pathology is thought to propagate from gut to brain via the vagus nerve, which innervates GI tract locations, including the appendix. Remarkably, α-synuclein aggregates in the appendix occur not only in PD patients, but are also present in healthy individuals. This has led to the proposal that in the appendix α-synuclein aggregates are not unique to PD. Moreover, the molecular events leading to PD and the mechanisms by which α-synuclein aggregates transfers from gut to brain may be identifiable in the human appendix. The influence of the appendix on GI inflammation, autoimmunity, microbiome storage, and the lymphatic system may be yet unexplored mechanisms by which the appendix contributes to PD. Overall, the appendix represents a promising tissue site to advance our understanding of PD pathobiology.

Topics: alpha-Synuclein; Animals; Appendix; Gastrointestinal Microbiome; Humans; Immune System; Inflammatory Bowel Diseases; Lymphatic System; Parkinson Disease

Parkinson's disease (PD) is a long-term degenerative disorder that affects predominately dopaminergic neurons in the substantia nigra, which mainly control movement. Alpha-synuclein (α-syn) is a major constituent of Lewy bodies that are reported to be the most important toxic species in the brain of PD patients. In this critical review, we highlight novel electrochemical biosensors that have been recently developed utilizing aptamers and antibodies in connection with various nanomaterials to study biomarkers related to PD such as α-syn. We also review several research articles that have utilized electrochemical biosensors to study the interaction of α-syn with biometals as well as small molecules such as clioquinol, (-)-epigallocatechin-3-gallate (EGCG) and baicalein. Due to the significant advances in nanomaterials in the past decade, electrochemical biosensors capable of detecting multiple biomarkers in clinically relevant samples in real-time have been achieved. This may facilitate the path towards commercialization of electrochemical biosensors for clinical applications and high-throughput screening of small molecules for structure-activity relationship (SAR) studies.

Topics: alpha-Synuclein; Antibodies; Aptamers, Nucleotide; Aptamers, Peptide; Biomarkers; Biosensing Techniques; DNA; Electrochemical Techniques; Humans; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by loss of dopaminergic (DA) neurons in the dense part of the substantia nigra (SNpc). Postmortem analysis of PD patients and experimental animal studies found that microglial cell activation and increased levels of pro-inflammatory factors were common features of PD brain tissue. At the same time, the invasion and accumulation of peripheric immune cells were detected in the brain of PD patients. In this paper, peripheral inflammation across the blood-brain barrier (BBB), the misfolded α-synuclein (α-syn)-induced microglial cell activation and intracerebral inflammation in PD are summarized, providing potential therapeutic measures for delaying the onset of PD.

Topics: alpha-Synuclein; Animals; Blood-Brain Barrier; Dopaminergic Neurons; Humans; Inflammation; Microglia; Parkinson Disease; Substantia Nigra

Copper (Cu) and iron (Fe) are redox active metals essential for the regulation of cellular pathways that are fundamental for brain function, including neurotransmitter synthesis and release, neurotransmission, and protein turnover. Cu and Fe are tightly regulated by sophisticated homeostatic systems that tune the levels and localization of these redox active metals. The regulation of Cu and Fe necessitates their coordination to small organic molecules and metal chaperone proteins that restrict their reactions to specific protein centres, where Cu and Fe cycle between reduced (Fe

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyotrophic Lateral Sclerosis; Animals; Brain; Copper; Humans; Iron; Neuroprotective Agents; Parkinson Disease

Exosomes are extracellular vesicles produced by eukaryotic cells that are also found in most biological fluids and tissues. While they were initially thought to act as compartments for removal of cellular debris, they are now recognized as important tools for cell-to-cell communication and for the transfer of pathogens between the cells. They have attracted particular interest in neurodegenerative diseases for their potential role in transferring prion-like proteins between neurons, and in Parkinson's disease (PD), they have been shown to spread oligomers of α-synuclein in the brain accelerating the progression of this pathology. A potential neuroprotective role of exosomes has also been equally proposed in PD as they could limit the toxicity of α-synuclein by clearing them out of the cells. Exosomes have also attracted considerable attention for use as drug vehicles. Being nonimmunogenic in nature, they provide an unprecedented opportunity to enhance the delivery of incorporated drugs to target cells. In this review, we discuss current knowledge about the potential neurotoxic and neuroprotective role of exosomes and their potential application as drug delivery systems in PD.

Topics: alpha-Synuclein; Drug Delivery Systems; Exosomes; Humans; Neuroprotection; Neurotoxins; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide, mainly affecting the elderly. The disease progresses gradually, with core motor presentations and a multitude of non-motor manifestations. There are two neuropathological hallmarks of PD, the dopaminergic neuronal loss and the alpha-synuclein-containing Lewy body inclusions in the substantia nigra. While the exact pathomechanisms of PD remain unclear, genetic investigations have revealed evidence of the involvement of mitochondrial function, alpha-synuclein (α-syn) aggregation, and the endo-lysosomal system, in disease pathogenesis. Due to the high energy demand of dopaminergic neurons, mitochondria are of special importance acting as the cellular powerhouse. Mitochondrial dynamic fusion and fission, and autophagy quality control keep the mitochondrial network in a healthy state. Should defects of the organelle occur, a variety of reactions would ensue at the cellular level, including disrupted mitochondrial respiratory network and perturbed calcium homeostasis, possibly resulting in cellular death. Meanwhile, α-syn is a presynaptic protein that helps regulate synaptic vesicle transportation and endocytosis. Its misfolding into oligomeric sheets and fibrillation is toxic to the mitochondria and neurons. Increased cellular oxidative stress leads to α-syn accumulation, causing mitochondrial dysfunction. The proteasome and endo-lysosomal systems function to regulate damage and unwanted waste management within the cell while facilitating the quality control of mitochondria and α-syn. This review will analyze the biological functions and interactions between mitochondria, α-syn, and the endo-lysosomal system in the pathogenesis of PD.

Topics: alpha-Synuclein; Animals; Biological Transport, Active; Dopaminergic Neurons; Electron Transport; Endosomes; Humans; Lysosomes; Mitochondria; Parkinson Disease; Synaptic Vesicles

Parkinson's disease (PD) is a neurodegenerative disorder that currently affects 1% of the population over the age of 60 years, for which no disease-modifying treatments exist. This lack of effective treatments is related to the advanced stage of neurodegeneration existing at the time of diagnosis. Thus, the identification of early stage biomarkers is crucial. Biomarker discovery is often guided by the underlying molecular mechanisms leading to the pathology. One of the central pathways deregulated during PD, supported both by genetic and functional studies, is the autophagy-lysosomal pathway. Hence, this review presents different studies on the expression and activity of autophagic and lysosomal proteins, and their functional consequences, performed in peripheral human biospecimens. Although most biomarkers are inconsistent between studies, some of them, namely HSC70 levels in sporadic PD patients, and cathepsin D levels and glucocerebrosidase activity in PD patients carrying

Topics: alpha-Synuclein; Autophagy; Biomarkers; Cathepsin D; Glucosylceramidase; HSC70 Heat-Shock Proteins; Humans; Lysosomes; Parkinson Disease; Proteins

Genetic and genomic studies have advanced our knowledge of inherited Parkinson's disease (PD), however, the etiology and pathophysiology of idiopathic PD remain unclear. Herein, we perform a meta-analysis of 8 PD postmortem brain transcriptome studies by employing a multiscale network biology approach to delineate the gene-gene regulatory structures in the substantia nigra and determine key regulators of the PD transcriptomic networks. We identify STMN2, which encodes a stathmin family protein and is down-regulated in PD brains, as a key regulator functionally connected to known PD risk genes. Our network analysis predicts a function of human STMN2 in synaptic trafficking, which is validated in Stmn2-knockdown mouse dopaminergic neurons. Stmn2 reduction in the mouse midbrain causes dopaminergic neuron degeneration, phosphorylated α-synuclein elevation, and locomotor deficits. Our integrative analysis not only begins to elucidate the global landscape of PD transcriptomic networks but also pinpoints potential key regulators of PD pathogenic pathways.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Gene Expression Profiling; Gene Knockdown Techniques; Gene Regulatory Networks; Humans; Locomotion; Mice; Parkinson Disease; Phosphorylation; Stathmin; Substantia Nigra; Transcriptome

Neurodegenerative diseases are characterized by the aggregation and deposition of misfolded proteins in the brain, most prominently amyloid-β (Aβ), tau and α-synuclein (α-syn), and are thus referred to as proteinopathies. While tau is a hallmark of Alzheimer's disease (AD) and other non-AD tauopathies, and α-synuclein is the pathological feature of the spectrum of synucleinopathies including Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), the presence of co-pathologies is very frequent in all these diseases. Positive and synergistic associations between the different types of protein deposits have been reported, leading to worse prognosis and cognitive decline. A large variation in phenotypic clinical presentation of these diseases, largely due to the frequent presence of co-pathologies, makes differential diagnosis challenging. The observed clinico-pathological overlaps suggest common underlying mechanisms, in part due to shared genetic risk factors. The ε4 allele of the apolipoprotein (APOE) gene is one of the major genetic risk factors for the sporadic forms of proteinopathies, but the biological mechanisms linking APOE, tau and α-syn are not fully understood. This chapter describes current experimental evidence on the relationships between APOE variants, tau and α-syn, from clinical studies on fluid biomarkers and positron emission tomography (PET) imaging, and from basic experimental studies in cellular/molecular biology and animal models. The chapter focuses on recent advances and identifies knowledge gaps. In particular, no PET tracer for assessment of brain α-syn deposits is yet available, although it is subject of intense research and development, therefore experimental evidence on in vivo α-syn levels is based on measures in the cerebrospinal fluid (CSF) and plasma. Moreover, tau PET imaging studies comparing the patterns of tracer retention in synucleinopathies versus in other proteinopathies are scarce and much is still unknown regarding the relationships between APOE variants and fluid and/or imaging biomarkers of tau and α-syn. Further research incorporating multimodal imaging, fluid biomarkers and genetic factors will help elucidate the biological mechanisms underlying these proteinopathies, and contribute to differential diagnosis and patient stratification for clinical trials.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Apolipoproteins E; Biomarkers; Humans; Lewy Body Disease; Parkinson Disease; Synucleinopathies; tau Proteins

This review provides an update about cardiac sympathetic denervation in Lewy body diseases. The family of Lewy body diseases includes Parkinson's disease (PD), pure autonomic failure (PAF), and dementia with Lewy bodies (DLB). All three feature intra-neuronal cytoplasmic deposits of the protein, alpha-synuclein. Multiple system atrophy (MSA), the parkinsonian form of which can be difficult to distinguish from PD with orthostatic hypotension, involves glial cytoplasmic inclusions that contain alpha-synuclein. By now there is compelling neuroimaging, neuropathologic, and neurochemical evidence for cardiac sympathetic denervation in Lewy body diseases. In addition to denervation, there is decreased storage of catecholamines in the residual terminals. The degeneration develops in a centripetal, retrograde, "dying back" sequence. Across synucleinopathies the putamen and cardiac catecholaminergic lesions seem to occur independently of each other, whereas non-motor aspects of PD (e.g., anosmia, dementia, REM behavior disorder, OH) are associated with each other and with cardiac sympathetic denervation. Cardiac sympathetic denervation can be caused by synucleinopathy in inherited PD. According to the catecholaldehyde hypothesis, 3,4-dihydroxyphenylacetaldehyde (DOPAL), an intermediary metabolite of dopamine, causes or contributes to the death of catecholamine neurons, especially by interacting with proteins such as alpha-synuclein. DOPAL oxidizes spontaneously to DOPAL-quinone, which probably converts alpha-synuclein to its toxic oligomeric form. Decreasing DOPAL production and oxidation might slow the neurodegenerative process. Tracking cardiac sympathetic innervation over time could be the basis for a proof of principle experimental therapeutics trial targeting DOPAL.

Topics: 3,4-Dihydroxyphenylacetic Acid; alpha-Synuclein; Catecholamines; Dopamine; Heart; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Myocardium; Neuroimaging; Neurons; Parkinson Disease; Sympathetic Nervous System

Parkinson's disease is caused by complex interactions between environmental factors and a genetic predisposition. Environmental factors include exposure to pesticides and toxins, heavy metals and accumulation of iron and/or manganese in the brain. However, accumulating evidence indicates that gut-brain health and function are impaired in Parkinson's disease, often a decade before motor symptoms are diagnosed. We present the gut-brain theory of Parkinson's disease and summarise the peripheral and central nervous system pathology, gastrointestinal symptoms experienced by many Parkinson's patients, the route by which gut-brain dysfunction may occur and changes in gut microbiota that are associated with disease expression. Finally, we consider future gut-based treatments to prevent or slow down the progression of Parkinson's disease and explore whether this knowledge may highlight biomarkers to be included in complex algorithms in the future to assess a person's risk of developing Parkinson's disease.

Topics: alpha-Synuclein; Biomarkers; Brain; Gastrointestinal Microbiome; Humans; Neurosciences; Parkinson Disease

The hippocampus has a critical role in cognition and human memory and is one of the most studied structures in the brain. Despite more than 400 years of research, little is known about the Ammon's horn region cornu ammonis 2 (CA2) subfield in comparison to other subfield regions (CA1, CA3, and CA4). Recent findings have shown that CA2 plays a bigger role than previously thought. Here, we review understanding of hippocampus and CA2 ontogenesis, together with basic and clinical findings about the potential role of this region in neurodegenerative disease. The CA2 has widespread anatomical connectivity, unique signaling molecules, and intrinsic electrophysiological properties. Experimental studies using in vivo models found that the CA2 region has a role in cognition, especially in social memory and object recognition. In models of epilepsy and hypoxia, the CA2 exhibits higher resilience to cell death and hypoxia in comparison with neighboring regions, and while hippocampal atrophy remains poorly understood in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), findings from postmortem PD brain demonstrates clear accumulation of α-synuclein pathology in CA2, and the CA2-CA3 region shows relatively more atrophy compared with other hippocampal subfields. Taken together, there is a growing body of evidence suggesting that the CA2 can be an ideal hallmark with which to differentiate different neurodegenerative stages of PD. Here, we summarize these recent data and provide new perspectives/ideas for future investigations to unravel the contribution of the CA2 to neurodegenerative diseases.

Topics: alpha-Synuclein; Animals; Encephalitis; Hippocampus; Humans; Lewy Body Disease; Neurodegenerative Diseases; Parkinson Disease

The most abundantly present protein found in Lewy bodies, which is the pathological hallmark of Parkinson's disease, is α-synuclein. Native monomeric α-synuclein is localized within mitochondria, interacts with ATP synthase subunit, and enhances ATP synthase efficiency and mitochondrial function. Recently, an advanced study shows that the interaction of α-synuclein oligomer with ATP synthase switches its role from physiological to pathological, which leads to mitochondrial dysfunction.

Topics: alpha-Synuclein; Animals; Humans; Lewy Bodies; Mitochondrial Diseases; Mitochondrial Proton-Translocating ATPases; Parkinson Disease; Protein Binding

Parkinson's disease is pathologically characterized by the degeneration of dopaminergic neurons in the substantia nigra and the accumulation of neuronal cytoplasmic inclusions known as Lewy bodies, which are primarily composed of α-synuclein. Post-translational modifications of α-synuclein induced by nitrative stress have been linked to neurodegeneration. Here, we review the concept of α-synuclein nitration and its biological consequences. We also discuss the pathological roles of nitrated α-synuclein and their potential clinical implications in Parkinson's disease.

Topics: alpha-Synuclein; Animals; Brain; Humans; Nitrosative Stress; Parkinson Disease; Protein Aggregates

Parkinson's disease (PD) is the second most common multifactorial neurodegenerative disorder affecting 3% of population during elder age. The loss of substantia nigra, pars compacta (SNpc) neurons and deficiency of striatal dopaminergic neurons produces stables motor deficient. Further, increase alpha-synuclein accumulation, mitochondrial dysfunction, oxidative stress, excitotoxicity, and neuroinflammation plays a crucial role in the pathogenesis of PD. Alpha-synuclein protein encodes for SNCA gene and disturbs the normal physiological neuronal signaling via altering mitochondrial homeostasis. The level of α-synuclein is increased in both normal aging and PD brain to a greater extent and secondly reduced clearance results in accumulation of Lewy bodies (LB). Emerging evidences indicate that mitochondrial dysfunction might be a common cause but pathological insult through protein misfolding, aggregation, and accumulation leads to neuronal apoptosis. The observation supporting that expression of DJ-1, LLRK2, PARKIN, PINK1, and excessive excitotoxicity mediated by dysbalance between GABA and glutamate reduced mitochondrial functioning and increased neurotoxicity. Therefore, the present review summarizes the various pathological mechanisms and also explores the therapeutic strategies which could be useful to ameliorate movement disorder like Parkinsonism.

Topics: alpha-Synuclein; Animals; Disease Management; Dopaminergic Neurons; Humans; Mitochondria; Oxidative Stress; Parkinson Disease; Ubiquitin-Protein Ligases

Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α-synuclein and LRRK2 pathogenic mutations. While α-synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK2 encodes a multidomain dual-enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggest these unlikely partners do interact in important ways in disease, both within cells that express both LRRK2 and α-synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK2 and disease can be understood in part through LRRK2 kinase activity (phosphotransferase activity), α-synuclein toxicity is multilayered and plausibly interacts with LRRK2 kinase activity in several ways. We discuss common protein interactors like 14-3-3s that may regulate α-synuclein and LRRK2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α-synuclein expression and LRRK2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD.

Topics: alpha-Synuclein; Animals; Brain; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Nerve Degeneration; Neurons; Parkinson Disease

Amyloid formation is a pathological hallmark of many neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's. While it is unknown how these disorders are initiated, in vitro and cellular experiments confirm the importance of membranes. Ubiquitous in vivo, membranes induce conformational changes in amyloidogenic proteins and in some cases, facilitate aggregation. Reciprocally, perturbations in the bilayer structure can be induced by amyloid formation. Here, we review studies in the last 10 years describing α-synuclein (α-syn) and its interactions with membranes, detailing the roles of anionic and zwitterionic lipids in aggregation, and their contribution to Parkinson's disease. We summarize the impact of α-syn - comparing monomeric, oligomeric, and fibrillar forms - on membrane structure, and the effect of membrane remodeling on amyloid formation. Finally, perspective on future studies investigating the interplay between α-syn aggregation and membranes is discussed. This article is part of a Special Issue entitled: Amyloids.

Topics: alpha-Synuclein; Amyloid; Animals; Cell Membrane; Humans; Lipid Metabolism; Parkinson Disease; Protein Aggregation, Pathological

Alpha synuclein (αS) is a ~14 kDa intrinsically disordered protein. Decades of research have increased our knowledge on αS yet its physiological function remains largely elusive. The conversion of monomeric αS into oligomers and amyloid fibrils is believed to play a central role of the pathology of Parkinson's disease (PD). It is becoming increasingly clear that the interactions of αS with cellular membranes are important for both αS's functional and pathogenic actions. Therefore, understanding interactions of αS with membranes seems critical to uncover functional or pathological mechanisms. This review summarizes our current knowledge of how physicochemical properties of phospholipid membranes affect the binding and aggregation of αS species and gives an overview of how post-translational modifications and point mutations in αS affect phospholipid membrane binding and protein aggregation. We discuss the disruptive effects resulting from the interaction of αS aggregate species with membranes and highlight current approaches and hypotheses that seek to understand the pathogenic and/or protective role of αS in PD.

Topics: alpha-Synuclein; Amyloid; Animals; Cell Membrane; Humans; Lipid Bilayers; Parkinson Disease; Phospholipids; Protein Aggregation, Pathological

We hypothesize that Parkinson's disease (PD) pathogenesis can be divided into three temporal phases. During the first phase, 'triggers', such as viral infections or environmental toxins, spark the disease process in the brain and/or peripheral tissues. Triggers alone, however, may be insufficient, requiring 'facilitators' like peripheral inflammation for PD pathology to develop. Once the disease manifests, 'aggravators' spur further neurodegeneration and exacerbate symptoms. Aggravators are proposed to include impaired autophagy and cell-to-cell propagation of α-synuclein pathology. We believe clinical trials need to consider these three phases and target potential therapies at the appropriate stage of the disease process in order to be effective.

Topics: alpha-Synuclein; Animals; Autophagy; Brain; Disease Models, Animal; Humans; Neurons; Parkinson Disease

Parkinsons disease (PD) is a progressive neurodegenerative disease with substantial and growing socio-economic burden. In this multifactorial disease, aging, environmental, and genetic factors contribute to neurodegeneration and dopamine (DA) deficiency in the brain. Treatments aimed at DA restoration provide symptomatic relief, however, no disease modifying treatments are available, and PD remains incurable to date. Mathematical modeling can help understand such complex multifactorial neurological diseases. We review mathematical modeling efforts in PD with a focus on mechanistic models of pathogenic processes. We consider models of α-synuclein (Asyn) aggregation, feedbacks among Asyn, DA, and mitochondria and proteolytic systems, as well as pathology propagation through the brain. We hope that critical understanding of existing literature will pave the way to the development of quantitative systems pharmacology models to aid PD drug discovery and development.

Topics: alpha-Synuclein; Brain; Dopamine; Humans; Mitochondria; Models, Biological; Parkinson Disease

α-Synuclein, the major component of Lewy bodies (LBs) and Lewy neurites (LNs), is expressed in presynapses under physiologically normal conditions and is involved in synaptic function. Abnormal intracellular aggregates of misfolded α-synuclein such as LBs and LNs are pathological hallmarks of synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). According to previous studies using pathological models overexpressing α-synuclein, high expression of this protein in neurons is a critical risk factor for neurodegeneration. Therefore, it is important to know the endogenous expression levels of α-synuclein in each neuronal cell type. We previously reported differential expression profiles of α-synuclein in vitro and in vivo. In the wild-type mouse brain, particularly in vulnerable regions affected during the progression of idiopathic PD, α-synuclein is highly expressed in neuronal cell bodies of some early PD-affected regions, such as the olfactory bulb, the dorsal motor nucleus of the vagus, and the substantia nigra pars compacta. Synaptic expression of α-synuclein is mostly accompanied by expression of vesicular glutamate transporter-1, an excitatory synapse marker protein. In contrast, α-synuclein expression in inhibitory synapses differs among brain regions. Recently accumulated evidence indicates the close relationship between differential expression profiles of α-synuclein and selective vulnerability of certain neuronal populations. Further studies on the regulation of α-synuclein expression will help to understand the mechanism of LB pathology and provide an innovative therapeutic strategy to prevent PD and DLB onset.

Topics: alpha-Synuclein; Animals; Brain; Gene Expression Regulation; Humans; Lewy Bodies; Lewy Body Disease; Mice; Neurons; Parkinson Disease; Protein Folding

Disease modification remains a major unmet need in Parkinson's disease (PD) therapeutics. Despite multiple attempts, not a single study has yet been successful, perhaps due to our incomplete understanding of the underlying disease mechanisms. Genetic and epidemiologic studies of the last decade have substantially increased our comprehension of the etiology of PD. Once considered a pure sporadic disease, the discovery of familial mutations provided the initial paradigm shift and it is now widely accepted that PD has a substantial genetic component. These genetic discoveries have allowed the development of novel therapeutics aimed at halting or slowing the underlying disease process, rather than just ameliorating symptoms. Here, we discuss the latest advances in therapeutics based on three genetic discoveries (SNCA, LRRK2 and GBA) that are currently reaching the clinical arena and outline the challenges of therapeutic development of genetically targeted therapeutics.

Topics: alpha-Synuclein; Biological Therapy; Glucosylceramidase; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Parkinson Disease

Diagnostic biomarkers are measures that detect or confirm the presence of a disease or identify individuals with a subtype of the disease. For Parkinson's disease, unlike other neurodegenerative diseases such as Alzheimer's disease and Creutzfeldt-Jakob disease, diagnostic biomarkers remain elusive as none are yet available or approved for clinical use. A biomarker to diagnose early or prodromal Parkinson's disease with high accuracy would significantly enhance clinical practice as well as advance clinical therapeutic trials. Multiple lines of evidence support a role of α-synuclein in the pathophysiology of Parkinson's disease and hence major ongoing efforts to identify biomarkers for Parkinson's disease are aimed at measuring α-synuclein in peripheral tissues and biofluids, including cerebrospinal fluid. This work is still in the early stages of biomarker development and has been accompanied by both losses and victories. Here, α-synuclein in cerebrospinal fluid as a diagnostic marker for Parkinson's disease is reviewed, including measures of total α-synuclein, oligomeric and phosphorylated α-synuclein, and seeding activity of α-synuclein.

Topics: alpha-Synuclein; Biomarkers; Humans; Parkinson Disease

Estimates of the accuracy of clinical diagnosis of Parkinson's disease (PD) range between 46% and 90%, the accuracy of diagnosis dependent on prolonged clinical observation and clinical response to levodopa. For this reason, we need reliable diagnostic biomarkers. The cardinal hallmark of PD is alpha-synuclein aggregation in the brain. Demonstrating pathological alpha-synuclein in live patients would be useful for identifying and monitoring PD patients. By autopsy studies and in vivo studies, the presence of alpha-synuclein has been demonstrated even outside the central nervous system and the gastro-enteric tract appears to be the most promising candidate tissue for biopsy-taking and the esophagus and salivary glands appear to be the area with the highest concentration of alpha-synuclein. The purpose of our study is to conduct a review to determine the utility of salivary gland biopsy for the histological diagnosis of PD. A computerized medline study was carried out through the use of pubmed: using the MeSH terms: 'salivary gland biopsy for PD', 'PD and dysphagia', 'alpha-synuclein and salivary gland'. We found 9 articles about minor salivary glands and submandibular gland biopsy for diagnosis of PD. According to the results of this review, the submandibular gland biopsy is the test with the increased sensitivity and specificity compared to the biopsy of the minor salivary glands (sensitivity: 0.85 and 0.37 respectability and specificity: 0.96 and 0.94 respectively). New studies are necessary on a wider population to confirm these results.

Topics: alpha-Synuclein; Biomarkers; Humans; Parkinson Disease; Salivary Glands

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD), and the most prevalent movement disorder. PD is characterized by dopaminergic neurodegeneration in the substantia nigra, but its etiology has yet to be established. Among several genetic variants contributing to PD pathogenesis, α-synuclein and leucine-rich repeat kinase (LRRK2) are widely associated with neuropathological phenotypes in familial and sporadic PD. α-Synuclein and LRRK2 found in Lewy bodies, a pathogenic hallmark of PD, are often posttranslationally modified. As posttranslational modifications (PTMs) are key processes in regulating the stability, localization, and function of proteins, PTMs have emerged as important modulators of α-synuclein and LRRK2 pathology. Aberrant PTMs altering phosphorylation, ubiquitination, nitration and truncation of these proteins promote PD pathogenesis, while other PTMs such as sumoylation may be protective. Although the causes of many aberrant PTMs are unknown, environmental risk factors may contribute to their aberrancy. Environmental toxicants such as rotenone and paraquat have been shown to interact with these proteins and promote their abnormal PTMs. Notably, manganese (Mn) exposure leads to a PD-like neurological disorder referred to as manganism-and induces pathogenic PTMs of α-synuclein and LRRK2. In this review, we highlight the role of PTMs of α-synuclein and LRRK2 in PD pathogenesis and discuss the impact of environmental risk factors on their aberrancy.

Topics: alpha-Synuclein; Animals; Gene-Environment Interaction; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Bodies; Parkinson Disease; Protein Processing, Post-Translational

The discovery of genetic forms of Parkinson's disease (PD) has highlighted the importance of the autophagy/lysosomal and mitochondrial/oxidative stress pathways in disease pathogenesis. However, recently identified PD-linked genes, including DNAJC6 (auxilin), SYNJ1 (synaptojanin 1), and the PD risk gene SH3GL2 (endophilin A1), have also highlighted disruptions in synaptic vesicle endocytosis (SVE) as a significant contributor to disease pathogenesis. Additionally, the roles of other PD genes such as LRRK2, PRKN, and VPS35 in the regulation of SVE are beginning to emerge. Here we discuss the recent work on the contribution of dysfunctional SVE to midbrain dopaminergic neurons' selective vulnerability and highlight pathways that demonstrate the interplay of synaptic, mitochondrial, and lysosomal dysfunction in the pathogenesis of PD.

Topics: alpha-Synuclein; Animals; Autophagy; Dopamine; Dopaminergic Neurons; Endocytosis; Genetic Predisposition to Disease; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lysosomes; Mitochondria; Oxidative Stress; Parkinson Disease; Synaptic Vesicles

After Alzheimer's disease, Parkinson's disease (PD) is the second most prevalent and incidental neurodegenerative disorder, affecting more than 2% of the population older than 65 years old. Since it was first described 200 years ago by Dr James Parkinson, great steps have been made in the understanding of the pathology. However, the cause(s) that initiates and perpetuates the neurodegenerative process is (are) still not clear. Thus, early diagnosis is not available, nor are there efficient therapies that can stop neurodegeneration. PD clinical features are defined by motor (like bradykinesia, resting tremor, gait impairment) and non-motor symptoms (like constipation, apathy, fathigue, olfactory dysfunction, depression and cognitive decline) that get more severe as the disease advances. Neuropathological hallmarks comprise selective loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) and Lewy bodies (LB) in different nuclei of the nervous system. Numerous studies have shown that these pathological features are aggravated by the confluence of other contributing factors, such as a genetic component, exposure to environmental toxins, mitochondrial dysfunction, increase of oxidative stress, calcium imbalance and chronic neuroinflammation, among others. Here, we provide a summary of the actual state of PD's pathology, the most studied molecular mechanisms, classic and novel therapeutic strategies and diagnosis methods, especially highlighting recent advances in these 200 years.

Topics: alpha-Synuclein; Animals; Calcium; Disease Progression; Dopamine; Genetic Predisposition to Disease; Genetic Therapy; History, 19th Century; History, 20th Century; History, 21st Century; Homeostasis; Humans; Inflammation; Lewy Bodies; Mitochondria; Motor Skills; Oxidative Stress; Parkinson Disease; Proteasome Endopeptidase Complex; Reactive Oxygen Species; Risk Factors; Ubiquitin; Ubiquitin-Protein Ligases

In Parkinson's disease (PD), there is a wide field of recent and ongoing search for useful biomarkers for early and differential diagnosis, disease monitoring or subtype characterization. Up to now, no biofluid biomarker has entered the daily clinical routine. Cerebrospinal fluid (CSF) is often used as a source for biomarker development in different neurological disorders because it reflects changes in central-nervous system homeostasis. This review article gives an overview about different biomarker approaches in PD, mainly focusing on CSF analyses. Current state and future perspectives regarding classical protein markers like alpha‑synuclein, but also different "omics" techniques are described. In conclusion, technical advancements in the field already yielded promising results, but further multicenter trials with well-defined cohorts, standardized protocols and integrated data analysis of different modalities are needed before successful translation into routine clinical application.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Animals; Biomarkers; Diagnosis, Differential; Humans; Inflammation Mediators; Neurofilament Proteins; Parkinson Disease; Peptide Fragments

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by selective and progressive loss of dopaminergic neurons. Genetic and environmental risk factors are associated with this disease. The genetic factors are composed of approximately 20 genes, such as SNCA, parkin, PTEN-induced kinase1 (pink1), leucine-rich repeat kinase 2 (LRRK2), ATP13A2, MAPT, VPS35, and DJ-1, whereas the environmental factors consist of oxidative stress-induced toxins such as 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), rotenone, and paraquat. The analyses of their functions and mechanisms have provided important insights into the disease process, which has demonstrated that these factors cause oxidative damage and mitochondrial dysfunction. The most invaluable studies have been performed using disease model organisms, such as mice, fruit flies, and worms. Among them, Drosophila melanogaster has emerged as an excellent model organism to study both environmental and genetic factors and provide insights to the pathways relevant for PD pathogenesis, facilitating development of therapeutic strategies. In this review, we have focused on the fly model organism to summarize recent progress, including pathogenesis, neuroprotective compounds, and newer approaches. [BMB Reports 2019; 52(4): 250-258].

Topics: Adenosine Triphosphatases; alpha-Synuclein; Animals; Disease Models, Animal; Dopaminergic Neurons; Drosophila melanogaster; Drosophila Proteins; Hazardous Substances; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Membrane Proteins; Mitochondria; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease; Protein Deglycase DJ-1; Protein Serine-Threonine Kinases; Ubiquitin-Protein Ligases; Vesicular Transport Proteins

Alpha-synuclein (α-syn) is a small protein that, in neurons, localizes predominantly to presynaptic terminals. Due to elevated conformational plasticity, which can be affected by environmental factors, in addition to undergoing disorder-to-order transition upon interaction with different interactants, α-syn is counted among the intrinsically disordered proteins (IDPs) family. As with many other IDPs, α-syn is considered a hub protein. This function is particularly relevant at synaptic sites, where α-syn is abundant and interacts with many partners, such as monoamine transporters, cytoskeletal components, lipid membranes, chaperones and synaptic vesicles (SV)-associated proteins. These protein⁻protein and protein⁻lipid membrane interactions are crucial for synaptic functional homeostasis, and alterations in α-syn can cause disruption of this complex network, and thus a failure of the synaptic machinery. Alterations of the synaptic environment or post-translational modification of α-syn can induce its misfolding, resulting in the formation of oligomers or fibrillary aggregates. These α-syn species are thought to play a pathological role in neurodegenerative disorders with α-syn deposits such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are referred to as synucleinopathies. Here, we aim at revising the complex and promiscuous role of α-syn at synaptic terminals in order to decipher whether α-syn molecular interactants may influence its conformational state, contributing to its aggregation, or whether they are just affected by it.

Topics: alpha-Synuclein; Animals; Humans; Multiple System Atrophy; Neurotransmitter Agents; Parkinson Disease; Protein Binding; Synapses

Idiopathic REM sleep behavior disorder (iRBD) is one of the most significant prodromal manifestations of synucleinopathies. Different predictive biomarkers for iRBD conversion have been investigated, but scarce data are present in literature about the predictive role of cerebrospinal fluid (CSF) biomarkers. In this review, we focus on CSF biomarkers in patients with both iRBD and RBD associated with synucleinopathies to explore their potential predictive power.. Recent studies revealed that CSF α-synuclein levels are higher in Parkinson's disease (PD) patients with RBD compared to those without RBD, even if α-synuclein does not seem to predict conversion of iRBD into PD. In the Parkinson Progression Marker Initiative (PPMI) cohort, early PD patients with RBD show lower CSF Aβ

Topics: Aged; alpha-Synuclein; Biomarkers; Cognitive Dysfunction; Disease Progression; Early Diagnosis; Female; Humans; Male; Middle Aged; Parkinson Disease; REM Sleep Behavior Disorder; Synucleinopathies

Accumulation of α-synuclein (α-syn) species in dopaminergic neurons is one of the main hallmarks of Parkinson's disease (PD). Several factors have been associated with α-syn aggregation process, including an impairment of the proper protein degradation, which might drive the neurons toward an alternative and/or additional clearance mechanism that involves the release of undigested material from the cell. It has been reported that extracellular α-syn, released by stressed and/or degenerating neurons, might widely contribute to the neuronal toxicity and degeneration. Therefore, the uptake and clearance of misfolded/aggregated proteins is a key process to control extracellular deposition of α-syn aggregates, the spreading and progression of the disease. All the main brain cell types, neurons, astrocytes and microglia are able to internalize and degrade extracellular α-syn, however, glial cells appear to be the most efficient scavengers. Accumulating evidence indicates that the endocytosis of α-syn species might be conformation-sensitive, cell- and receptor-type specific, making the scenario highly complex. In this review, we will shed light on the different endocytosis mechanisms and receptors recruited for the uptake and clearance of pathological α-syn forms with a special focus on glial cells. Moreover, we will discuss how PD-related genes, in addition to α-syn itself, may alter the endo-lysosomal pathway causing an impairment of clearance, which, in turn, lead to accumulation of toxic species, dysfunctions of glia physiology and progression of the disease.

Topics: alpha-Synuclein; Animals; Endocytosis; Endosomes; Humans; Lysosomes; Neuroglia; Parkinson Disease

Spread of α-synuclein pathology from the peripheral to central nervous system may be an important etiological factor in Parkinson's disease, although there are some unanswered questions about its correlation with neuronal loss. Experimental evidence has highlighted the gastrointestinal tract as a potential starting point for aggregated α-synuclein, with the vagus nerve acting as a "highway" by which pathology may be transmitted to the lower brain stem. This review begins by highlighting the key studies demonstrating that α-synuclein pathology has the ability to spread from certain sites in the gastrointestinal tract to the brain (and vice versa). We go on to assess the recent epidemiological studies that have shown that vagotomy and appendectomy may have the potential to reduce the risk of developing Parkinson's disease. Finally, we discuss the factors in the gastrointestinal tract (such as dysbiosis of the gut microbiota, infection, and inflammation) that may trigger α-synuclein aggregation in the first place, as well as other potential mechanisms underlying the distribution of α-synuclein pathology in the brain. © 2019 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Animals; Brain; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Parkinson Disease; Vagus Nerve

Exosomes, which are lipid bilayer membrane vesicles, have been implicated as carriers of biological macromolecules. In recent years, the functions of exosomes in the spreading of pathological conversion of proteins among neurons have drawn particular attention in Parkinson's disease research. Extracellular α-synuclein is proven to be associated with exosomes in vivo and in vitro. The contents of these exosomes may be altered during the pathological and clinical processes, serving as a potential target for biomarker development in Parkinson's disease. This Review highlights the current understanding of biogenesis and pathophysiological roles of exosomes. Meanwhile, exosomes are promising delivery vehicles. Artificial exosomes can be loaded with defined therapeutically active molecules, such as drugs, small interfering RNAs, long noncoding RNAs, and proteins to the brain, ensuring the site-specific targeting strategy to the recipient cells. Therefore, we will also discuss the potential applications of exosomes in developing modified exosome-based drug carrier systems to halt the pathologic propagation of Parkinson's disease.

Topics: alpha-Synuclein; Animals; Biomarkers; Blood-Brain Barrier; Brain; Drug Carriers; Exosomes; Forecasting; Humans; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. PD is characterized by the loss of dopaminergic neurons, primarily in brain regions that control motor functions, thereby leading to motor impairments in the patients. Pathological aggregated forms of the synaptic protein, α-synuclein (α-syn), are involved in the generation and progression of PD. In PD brains, α-syn accumulates inside neurons and propagates from cell-to-cell in a prion-like manner. In this review, we discuss the in vitro and in vivo models used to study the prion-like properties of α-syn and related findings. In particular, we focus on the different mechanisms of α-syn spreading, which could be relevant for the development of alternative therapeutic approaches for PD treatment.

Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Disease Progression; Dopaminergic Neurons; Humans; Neurodegenerative Diseases; Parkinson Disease; Prions

The etiology of Parkinson's disease (PD) is significantly influenced by disease-causing changes in the protein alpha-Synuclein (aSyn). It can trigger and promote intracellular stress and thereby impair the function of dopaminergic neurons. However, these damage mechanisms do not only extend to neuronal cells, but also affect most glial cell populations, such as astroglia and microglia, but also T lymphocytes, which can no longer maintain the homeostatic CNS milieu because they produce neuroinflammatory responses to aSyn pathology. Through precise neuropathological examination, molecular characterization of biomaterials, and the use of PET technology, it has been clearly demonstrated that neuroinflammation is involved in human PD. In this review, we provide an in-depth overview of the pathomechanisms that aSyn elicits in models of disease and focus on the affected glial cell and lymphocyte populations and their interaction with pathogenic aSyn species. The interplay between aSyn and glial cells is analyzed both in the basic research setting and in the context of human neuropathology. Ultimately, a strong rationale builds up to therapeutically reduce the burden of pathological aSyn in the CNS. The current antibody-based approaches to lower the amount of aSyn and thereby alleviate neuroinflammatory responses is finally discussed as novel therapeutic strategies for PD.

Topics: alpha-Synuclein; Brain; Clinical Trials as Topic; Humans; Immunotherapy; Inflammation; Parkinson Disease

Parkinson's disease (PD) is a common neurodegenerative disorder. To date, the diagnosis of PD relies mainly on clinical manifestations whereas neuropathological confirmation of the brain is only possible with postmortem studies. Neuronal loss in the substantia nigra pars compacta (SNc) associated with Lewy bodies/neurites is the pathological hallmark feature of PD. The major component of Lewy pathology (LP) is misfolded alpha-synuclein (α-SYN). There is evidence that the distribution of LP is not only limited to the brain but extends to peripheral tissues, including gastrointestinal tract, salivary glands, olfactory mucosa, skin, retina, adrenal gland, and heart. Sensitivity and specificity of α-SYN detection in PD vary greatly among studies due to methodological heterogeneity, such as sampling sites and size, tissue preparation, staining techniques, and antibodies used. Of note, α-SYN has also been found in preclinical and prodromal PD. Further in vivo studies focusing on favorable biopsy sites and standard techniques are needed to get better understanding of α-SYN deposits in preclinical, prodromal, and clinical PD.

Topics: Adrenal Glands; alpha-Synuclein; Animals; Brain; Gastrointestinal Tract; Humans; Myocardium; Olfactory Mucosa; Parkinson Disease

To date, there are no definitive biomarkers for diagnose Parkinson's disease (PD). The detection of α-synuclein (α-Syn) in plasma of PD patients has yielded promising but inconclusive results. To determine the performance of α-Syn as a diagnostic biomarker of PD, we used a meta-analysis.. We identified 173 studies through a systematic literature review. From those, only studies reporting data on total α-Syn levels were included in the meta-analysis (10 publications, 1302 participants). Quality of studies was assessed by Newcastle-Ottawa scale.. The α-Syn levels were significantly higher in PD patients than healthy controls (standardized mean difference [SMD] = 0.778, 95% confidence interval = 0.284 to 1.272, p = 0.002). Similar results were found after omitting any individual study from meta-analysis, with SMD ranges from 0.318 (95% CI = 0.064 to 0.572, p = 0.014) to 0.914 (95% CI = 0.349 to 1.480, p = 0.002). According to meta-regression analysis, increased mean patients age (slope = - 0.232, 95% CI = - 0.456 to - 0.008, p = 0.042), increased total number of participants (slope = - 0.007, 95% CI = - 0.013 to - 0.0004, p = 0.038), and increased percentage of males (slope = - 6.444, 95% CI = - 10.841 to - 2.047, p = 0.004) were associated with decreased SMD of α-Syn levels across studies. We did not find any significant association between the SMD in α-Syn levels and disease duration, disease severity, and quality of studies. Most of studies applied ELISA assays.. Total plasma α-Syn levels were higher in PD patients than controls. Analytical factors were important limitations.

Topics: alpha-Synuclein; Biomarkers; Humans; Parkinson Disease

Despite decades of research, accurate diagnosis of Parkinson's disease remains a challenge, and disease-modifying treatments are still lacking. Research into the early (presymptomatic) stages of Parkinson's disease and the discovery of novel biomarkers is of utmost importance to reduce this burden and to come to a more accurate diagnosis at the very onset of the disease. Many have speculated that non-motor symptoms could provide a breakthrough in the quest for early biomarkers of Parkinson's disease, including the visual disturbances and retinal abnormalities that are seen in the majority of Parkinson's disease patients. An expanding number of clinical studies have investigated the use of in vivo assessments of retinal structure, electrophysiological function, and vision-driven tasks as novel means for identifying patients at risk that need further neurological examination and for longitudinal follow-up of disease progression in Parkinson's disease patients. Often, the results of these studies have been interpreted in relation to α-synuclein deposits and dopamine deficiency in the retina, mirroring the defining pathological features of Parkinson's disease in the brain. To better understand the visual defects seen in Parkinson's disease patients and to propel the use of retinal changes as biomarkers for Parkinson's disease, however, more conclusive neuropathological evidence for the presence of retinal α-synuclein aggregates, and its relation to the cerebral α-synuclein burden, is urgently needed. This review provides a comprehensive and critical overview of the research conducted to unveil α-synuclein aggregates in the retina of Parkinson's disease patients and animal models, and thereby aims to aid the ongoing discussion about the potential use of the retinal changes and/or visual symptoms as biomarkers for Parkinson's disease.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Humans; Parkinson Disease; Retina

This study, taking the example of Alzheimer's and Parkinson's diseases, presents the experimental and human data that support the hypothesis that Aβ, tau, and α-synuclein may seed and propagate the pathology and consider the potential clinical consequences.. Aβ aggregates transmit Aβ pathology to experimental animals. Interhuman transmission of Aβ pathology has also been observed in iatrogenic Creutzfeldt-Jakob disease, or after dural graft. Tau aggregates also transmit the pathology to mice when injected in the brain and propagates along neuronal pathways. Evidence of interhuman transmission is weak. Finally α-synuclein aggregates, when injected in specific areas of the brain may recapitulate Lewy pathology of Parkinson's disease but there is currently no hint of human to human transmission.. Since the first evidence that at least Aβ pathology of Alzheimer's disease could be transmitted to the animal, data have accumulated indicating that misfolded proteins characteristic of neurodegenerative diseases may seed and propagate pathology in a prion-like manner. The term propagon has been proposed to describe those proteins that act as prions at different levels. Taking the example of Alzheimer's and Parkinson's diseases, the experimental and human data supporting the hypothesis that Aβ, tau, and α-synuclein are indeed propagons are presented with their clinical consequences.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Humans; Parkinson Disease; Prion Diseases; Prions; tau Proteins

The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain; Causality; Humans; Parkinson Disease; Protein Aggregation, Pathological

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is diagnosed largely on clinical grounds due to characteristic motor manifestations that result from the loss of nigrostriatal dopaminergic neurons. While traditional pharmacological approaches to enhance dopamine levels, such as with L-dopa, can be very effective initially, the chronic use of this dopamine precursor is commonly plagued with motor response complications. Additionally, with advancing disease, non-motor manifestations emerge, including psychosis and dementia that compound patient disability. The pathology includes hallmark intraneuronal inclusions known as Lewy bodies and Lewy neurites that contain fibrillar α-synuclein aggregates. Evidence has also accumulated that these aggregates can propagate across synaptically connected brain regions, a phenomenon that can explain the progressive nature of the disease and the emergence of additional symptoms over time. The level of α-synuclein is believed to play a critical role in its fibrillization and aggregation. Accordingly, nucleic acid-based therapeutics for PD include strategies to deliver dopamine biosynthetic enzymes to boost dopamine production or modulate the basal ganglia circuitry in order to improve motor symptoms. Delivery of trophic factors that might enhance the survival of dopamine neurons is another strategy that has been attempted. These gene therapy approaches utilize viral vectors and are delivered stereotaxically in the brain. Alternative disease-modifying strategies focus on downregulating the expression of the α-synuclein gene using various techniques, including modified antisense oligonucleotides, short hairpin RNA, short interfering RNA, and microRNA. The latter approaches also have implications for dementia with Lewy bodies. Other PD genes can also be targeted using nucleic acids. In this review, we detail these various strategies that are still experimental, and discuss the challenges and opportunities of nucleic acid-based therapeutics for PD.

Topics: alpha-Synuclein; Animals; Genetic Therapy; Humans; MicroRNAs; Oligonucleotides, Antisense; Parkinson Disease; RNA, Small Interfering

Non-cell-autonomous effects on neuronal cells are considered to be involved in the pathogenesis of neurodegenerative diseases but have yet to be mechanistically proven. In this issue of Stem Cell Reports, di Domenico et al. provide direct evidence that α-synuclein transferred from astrocytes exerts non-cell-autonomous neuronal dysfunction on dopaminergic neurons in Parkinson's disease (PD).

Topics: alpha-Synuclein; Animals; Astrocytes; Dopaminergic Neurons; Humans; Parkinson Disease; Stem Cells

The formation of cytotoxic intracellular protein aggregates is a pathological signature of multiple neurodegenerative diseases. The principle aggregating protein in Parkinson's disease (PD) and atypical Parkinson's diseases is α-synuclein (α-syn), which occurs in neural cytoplasmic inclusions. Several factors have been found to trigger α-syn aggregation, including raised calcium, iron, and copper. Transcriptional inducers have been explored to upregulate expression of endogenous metal-binding proteins as a potential neuroprotective strategy. The vitamin-D analogue, calcipotriol, induced increased expression of the neuronal vitamin D-dependent calcium-binding protein, calbindin-D28k, and this significantly decreased the occurrence of α-syn aggregates in cells with transiently raised intracellular free Ca, thereby increasing viability. More recently, the induction of endogenous expression of the Zn and Cu binding protein, metallothionein, by the glucocorticoid analogue, dexamethasone, gave a specific reduction in Cu-dependent α-syn aggregates. Fe accumulation has long been associated with PD. Intracellularly, Fe is regulated by interactions between the Fe storage protein ferritin and Fe transporters, such as poly(C)-binding protein 1. Analysis of the transcriptional regulation of Fe binding proteins may reveal potential inducers that could modulate Fe homoeostasis in disease. The current review highlights recent studies that suggest that transcriptional inducers may have potential as novel mechanism-based drugs against metal overload in PD.

Topics: alpha-Synuclein; Amino Acid Sequence; Homeostasis; Humans; Metals; Neuroprotection; Parkinson Disease; Protein Binding

The accumulation of misfolded α-synuclein in the brain is associated with Parkinson's disease. However, the association between gut α-synuclein and PD and diagnostic value of α-synuclein in the gut still remain controversial.. A literature search from inception to June 2018 was conducted, yielding 21 studies eligible for a systematic review and meta-analysis. We included studies that reported data on gut α-synuclein or phosphorylated α-synuclein in patients with PD and controls. The odds ratio(OR) was pooled using random-effect models, and heterogeneity was reported as I. The database search yielded 395 results, of which 21 studies were deemed relevant. The PD group had a pooled OR of 10.01 (95% CI: 3.15-31.82, I. Heterogeneity was high in most of the studies. This systematic review and meta-analysis confirmed a high degree of association between gut α-synuclein and PD, which suggested that gut α-synuclein is a potential therapeutic intervention. The measurement of gut α-synuclein alone could lead to the underdiagnosis of PD. Future research combining gut α-synuclein with other biochemical markers could improve the standardization of current assays.

Topics: alpha-Synuclein; Biomarkers; Brain; Colon; Gastrointestinal Tract; Humans; Odds Ratio; Parkinson Disease; Sensitivity and Specificity

Neurodegenerative disorders are among the most studied issues both in medicine and pharmacy. Despite long and extensive research, there is no effective treatment prescribed for such diseases, including Alzheimer's or Parkinson's. Available data exposes their multi-faceted character that requires a complex and multidirectional approach to treatment. In this case, the most important challenge is to understand the neurodegenerative mechanisms, which should permit the development of more elaborate and effective therapies. In the submitted review, iron and zinc are discussed as important and perfectly possible neurodegenerative factors behind Alzheimer's and Parkinson's diseases. It is commonly known that these elements are present in living organisms and are essential for the proper operation of the body. Still, their influence is positive only when their proper balance is maintained. Otherwise, when any imbalance occurs, this can eventuate in numerous disturbances, among them oxidative stress, accumulation of amyloid β and the formation of neurofibrillary tangles, let alone the increase in α-synuclein concentration. At the same time, available research data reveals certain discrepancies in approaching metal ions as either impassive, helpful, or negative factors influencing the development of neurodegenerative changes. This review outlines selected neurodegenerative disorders, highlights the role of iron and zinc in the human body and discusses cases of their imbalance leading to neurodegenerative changes as shown in vitro and in vivo studies as well as through relevant mechanisms.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Ions; Iron; Oxidative Stress; Parkinson Disease; Zinc

α-Synuclein (α-Syn) has been extensively studied for its structural and biophysical properties owing to its pathophysiological role in Parkinson's disease (PD). Lewy bodies and Lewy neurites are the pathological hallmarks of PD and contain α-Syn aggregates as their major component. It was therefore hypothesized that α-Syn aggregation is actively associated with PD pathogenesis. The central role of α-Syn aggregation in PD is further supported by the identification of point mutations in α-Syn protein associated with rare familial forms of PD. However, the correlation between aggregation propensities of α-Syn mutants and their association with PD phenotype is not straightforward. Recent evidence suggested that oligomers, formed during the initial stages of aggregation, are the potent neurotoxic species causing cell death in PD. However, the heterogeneous and unstable nature of these oligomers limit their detailed characterization. α-Syn fibrils, on the contrary, are shown to be the infectious agents and propagate in a prion-like manner. Although α-Syn is an intrinsically disordered protein, it exhibits remarkable conformational plasticity by adopting a range of structural conformations under different environmental conditions. In this review, we focus on the structural and functional aspects of α-Syn and role of potential factors that may contribute to the underlying mechanism of synucleinopathies. This information will help to identify novel targets and develop specific therapeutic strategies to combat Parkinson's and other protein aggregation related neurodegenerative diseases.

Topics: alpha-Synuclein; Humans; Intrinsically Disordered Proteins; Lewy Bodies; Neurites; Parkinson Disease; Point Mutation; Protein Aggregates; Protein Folding; Structure-Activity Relationship

Evidence from a variety of studies implicates a role for the adaptive immune system in Parkinson's disease (PD). Similar to multiple sclerosis (MS) patients who display a high number of T cells in the brain attacking oligodendrocytes, PD patients show higher numbers of T cells in the ventral midbrain than healthy, age-matched controls. Mouse models of the disease also show the presence of T cells in the brain. The role of these infiltrating T cells in the propagation of disease is controversial; however, recent studies indicate that they may be autoreactive in nature, recognizing disease-altered self-proteins as foreign antigens. T cells of PD patients can generate an autoimmune response to α-synuclein, a protein that is aggregated in PD. α-Synuclein and other proteins are post-translationally modified in an environment in which protein processing is altered, possibly leading to the generation of neo-epitopes, or self-peptides that have not been identified by the host immune system as non-foreign. Infiltrating T cells may also be responding to such modified proteins. Genome-wide association studies (GWAS) have shown associations of PD with haplotypes of major histocompatibility complex (MHC) class II genes, and a polymorphism in a non-coding region that may increase MHC class II in PD patients. We speculate that the inflammation observed in PD may play both pathogenic and protective roles. Future studies on the adaptive immune system in neurodegenerative disorders may elucidate steps in disease pathogenesis and assist with the development of both biomarkers and treatments.

Topics: alpha-Synuclein; Animals; Autoimmunity; Brain; Humans; Inflammation; Parkinson Disease; T-Lymphocytes

Parkinson's Disease (PD) is typically classified as a neurodegenerative disease affecting the motor system. Recent evidence, however, has uncovered the presence of Lewy bodies in locations outside the CNS, in direct contact with the external environment, including the olfactory bulbs and the enteric nervous system. This, combined with the ability of alpha-synuclein (αS) to propagate in a prion-like manner, has supported the hypothesis that the resident microbial community, commonly referred to as microbiota, might play a causative role in the development of PD. In this article, we will be reviewing current knowledge on the importance of the microbiota in PD pathology, concentrating our investigation on mechanisms of microbiota-host interactions that might become harmful and favor the onset of PD. Such processes, which include the secretion of bacterial amyloid proteins or other metabolites, may influence the aggregation propensity of

Topics: alpha-Synuclein; Animals; Humans; Microbiota; Molecular Mimicry; Parkinson Disease

Lewy body diseases share clinical, pathological, genetic and biochemical signatures, and are regarded as a highly heterogeneous group of neurodegenerative disorders. Inclusive of Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), controversy still exists as to whether they should be considered as separate disease entities or as part of the same disease continuum. Here we discuss emerging knowledge relating to both clinical, and neuropathological differences and consider current biomarker strategies as we try to improve our diagnostic capabilities and design of disease modifying therapeutics for this group of debilitating neurodegenerative disorders. This article is part of the Special Issue "Synuclein".

Topics: alpha-Synuclein; Apolipoprotein E4; Biomarkers; Brain; Dementia; Diagnosis, Differential; Disease Progression; Forecasting; Glucosylceramidase; Humans; Lewy Bodies; Lewy Body Disease; Mental Status and Dementia Tests; Neurodegenerative Diseases; Parkinson Disease; Symptom Assessment; Synucleinopathies

Among the progressive neurodegenerative disorders, Parkinson's disease (PD) is the second most common. Different factors have critical role in pathophysiology of PD such as apoptosis pathways, inflammatory cytokines, oxidative stress, and neurotransmitters and its receptors abnormalities. Acupuncture and electroacupuncture were considered as nondrug therapies for PD. Although numerous studies has been conducted for assessing the mechanism underlying electroacupuncture and acupuncture, various principal aspects of these treatment procedures remain not well-known. There have also been few investigations on the molecular mechanism of acupuncture and electroacupuncture therapy effects in PD. This review evaluates the effects of electroacupuncture and acupuncture on the molecular mechanism in PD.

Topics: Acupuncture Therapy; alpha-Synuclein; Apoptosis; Electroacupuncture; Humans; Oxidative Stress; Parkinson Disease

Parkinson's disease (PD), the second most common neurodegenerative movement disorder, is characterized by progressive motor and non-motor symptoms [1]. Despite treatment with pharmacologic and surgical therapies, the disease will continue to relentlessly advance. Hence, there is a great deal of interest in potential disease-modifying therapies with the hope that the neurodegenerative process can be slowed or halted. The purpose of this review is to highlight the role toxic α-synuclein (α-syn) plays in PD pathogenesis and critically review the relevant literature about therapeutic modalities targeting α-syn. Toxic α-syn plays a key role in PD pathogenesis, disrupting important cellular functions, and, thus, targeting α-syn is a reasonable disease-modifying strategy. Current approaches under investigation include decreasing α-syn production with RNA interference (RNAi), inhibiting α-syn aggregation, promoting intracellular degradation of α-syn aggregates (via enhancing autophagy and enhancing lysosomal degradation), and promoting extracellular degradation of α-syn via active and passive immunization.

Topics: alpha-Synuclein; Autophagy; Enteric Nervous System; Gene Expression Regulation; Humans; Molecular Targeted Therapy; Mutation; Parkinson Disease; Protein Aggregates; Receptors, Adrenergic, beta

Many neurodegenerative diseases are characterized by progressive loss of neurons and abnormal protein accumulation, including amyloid (A)β and tau in Alzheimer's disease and Lewy bodies and α-synuclein (α-syn) in Parkinson's disease (PD). Recent evidence suggests that adaptive immunity plays an important role in PD, and that anti-α-syn antibodies can be used as therapy in neurodegenerative diseases; monoclonal antibodies were shown to inhibit α-syn propagation and aggregation in PD models and patients. In this review, we summarize the different pathological states of α-syn, including gene mutations, truncation, phosphorylation, and the high molecular weight form, and describe the specific antibodies that recognize the α-syn monomer or oligomer, some of which have been tested in clinic trials. We also discuss future research directions and potential targets in PD therapy.

Topics: alpha-Synuclein; Antibodies; Humans; Immunization, Passive; Immunotherapy, Active; Parkinson Disease

Synucleinopathies including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are characterized by the abnormal accumulation and propagation of α-synuclein (α-syn) pathology in the central and peripheral nervous system as Lewy bodies or glial cytoplasmic inclusions. Several antibodies against α-syn have been developed since it was first detected as the major component of Lewy bodies and glial cytoplasmic inclusions. Over the years, researchers have generated specific antibodies that alleviate the accumulation of intracellular aggregated α-syn and associated pathology in cellular and preclinical models of synucleinopathies. So far, antibodies have been the first choice as tools for research and diagnosis and currently, a wide variety of antibody fragments have been developed as an alternative to full-length antibodies for increasing its therapeutic usefulness. Recently, conformation specific antibody-based approaches have been found to be promising as therapeutic strategies, both to block α-syn aggregation and ameliorate the resultant cytotoxicity, and as diagnostic tools. In this review, we summarize different α-syn specific antibodies and provide their usefulness in tackling synucleinopathies. This article is part of the Special Issue "Synuclein".

Topics: alpha-Synuclein; Antibodies; Antibodies, Bispecific; Antibodies, Monoclonal; Antibody Specificity; Biomarkers; Delayed Diagnosis; Epitopes; Humans; Immunoglobulin Fragments; Immunologic Tests; Parkinson Disease; Protein Aggregation, Pathological; Protein Conformation; Protein Engineering; Recombinant Proteins; Single-Domain Antibodies; Synucleinopathies

The levels and conformers of alpha-synuclein are critical in the pathogenesis of Parkinson's Disease and related synucleinopathies. Homeostatic mechanisms in protein degradation and secretion have been identified as regulators of alpha-synuclein at different stages of its intracellular trafficking and transcellular propagation. Here we review pathways involved in the removal of various forms of alpha-synuclein from both the intracellular and extracellular environment. Proteasomes and lysosomes are likely to play complementary roles in the removal of intracellular alpha-synuclein species, in a manner that depends on alpha-synuclein post-translational modifications. Extracellular alpha-synuclein is cleared by extracellular proteolytic enzymes, or taken up by neighboring cells, especially microglia and astrocytes, and degraded within lysosomes. Exosomes, on the other hand, represent a vehicle for egress of excess burden of the intracellular protein, potentially contributing to the transfer of alpha-synuclein between cells. Dysfunction in any one of these clearance mechanisms, or a combination thereof, may be involved in the initiation or progression of Parkinson's disease, whereas targeting these pathways may offer an opportunity for therapeutic intervention. This article is part of the Special Issue "Synuclein".

Topics: alpha-Synuclein; Astrocytes; Disease Progression; Exosomes; Extracellular Fluid; Genetic Therapy; Humans; Immunotherapy; Intracellular Fluid; Lewy Bodies; Lysosomes; Microglia; Parkinson Disease; Phosphorylation; Proteasome Endopeptidase Complex; Protein Aggregation, Pathological; Protein Processing, Post-Translational; Proteolysis; Ubiquitination

Dystonia and Parkinson's disease are closely linked disorders sharing many pathophysiological overlaps. Dystonia can be seen in 30% or more of the patients suffering with PD and sometimes can precede the overt parkinsonism. The response of early dystonia to the introduction of dopamine replacement therapy (levodopa, dopamine agonists) is variable; dystonia commonly occurs in PD patients following levodopa initiation. Similarly, parkinsonism is commonly seen in patients with mutations in various DYT genes including those involved in the dopamine synthesis pathway. Pharmacological blockade of dopamine receptors can cause both tardive dystonia and parkinsonism and these movement disorders syndromes can occur in many other neurodegenerative, genetic, toxic and metabolic diseases. Pallidotomy in the past and currently deep brain stimulation largely involving the GPi are effective treatment options for both dystonia and parkinsonism. However, the physiological mechanisms underlying the response of these two different movement disorder syndromes are poorly understood. Interestingly, DBS for PD can cause dystonia such as blepharospasm and bilateral pallidal DBS for dystonia can result in features of parkinsonism. Advances in our understanding of these responses may provide better explanations for the relationship between dystonia and Parkinson's disease.

Topics: alpha-Synuclein; Deep Brain Stimulation; Dystonia; GTP Cyclohydrolase; Humans; Levodopa; Parkinson Disease

The identification of genetic forms of Parkinson's disease (PD) has tremendously expanded our understanding of the players and mechanisms involved. Mutations in the genes encoding for alpha-synuclein (aSyn), LRRK2, and tau have been associated with familial and sporadic forms of the disease. aSyn is the major component of Lewy bodies and Lewy neurites, which are pathognomonic protein inclusions in PD. Hyperphosphorylated tau protein accumulates in neurofibrillary tangles in the brains of Alzheimer's disease patients but is also seen in the brains of PD patients. LRRK2 is a complex multi-domain protein with kinase and GTPase enzymatic activity. Since aSyn and tau are phosphoproteins, we review the possible interplay between the three proteins. Understanding the interplay between LRRK2, aSyn and tau is extremely important, as this may enable the identification of novel targets and pathways for therapeutic intervention.

Topics: alpha-Synuclein; Alzheimer Disease; Brain; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Parkinson Disease; Phosphorylation; tau Proteins

Peripheral membrane proteins associate reversibly with biological membranes that, compared to protein binding partners, are structurally labile and devoid of specific binding pockets. Membranes in different subcellular compartments vary primarily in their chemical composition and physical properties, and recognition of these features is therefore critical for allowing such proteins to engage their proper membrane targets. Intrinsically disordered proteins (IDPs) are well-suited to accomplish this task using highly specific and low- to moderate-affinity interactions governed by recognition principles that are both similar to and different from those that mediate the membrane interactions of rigid proteins. IDPs have also evolved multiple mechanisms to regulate membrane (and other) interactions and achieve their impressive functional diversity. Moreover, IDP-membrane interactions may have a kinetic advantage in fast processes requiring rapid control of such interactions, such as synaptic transmission or signaling. Herein we review the biophysics, regulation and functional implications of IDP-membrane interactions and include a brief overview of some of the methods that can be used to study such interactions. At each step, we use the example of alpha-synuclein, a protein involved in the pathogenesis of Parkinson's disease and one of the best characterized membrane-binding IDP, to illustrate some of the principles discussed.

Topics: alpha-Synuclein; Animals; Cell Membrane; Humans; Intrinsically Disordered Proteins; Parkinson Disease

Parkinson's disease is the second most common neurodegenerative disorder worldwide. Neurodegeneration in this pathology is characterized by the loss of dopaminergic neurons in the substantia nigra, coupled with cytoplasmic inclusions known as Lewy bodies containing α-synuclein. The brain is an organ that concentrates metal ions, and there is emerging evidence that a break-down in metal homeostasis may be a critical factor in a variety of neurodegenerative diseases. α-synuclein has emerged as an important metal-binding protein in the brain, whereas these interactions play an important role in its aggregation and might represent a link between protein aggregation, oxidative damage, and neuronal cell loss. Additionally, α-synuclein undergoes several post-translational modifications that regulate its structure and physiological function, and may be linked to the aggregation and/or oligomer formation. This review is focused on the interaction of this protein with physiologically relevant metal ions, highlighting the cases where metal-AS interactions profile as key modulators for its structural, aggregation, and membrane-binding properties. The impact of α-synuclein phosphorylation and N-terminal acetylation in the metal-binding properties of the protein are also discussed, underscoring a potential interplay between PTMs and metal ion binding in regulating α-synuclein physiological functions and its role in pathology. This article is part of the Special Issue "Synuclein".

Topics: Acetylation; alpha-Synuclein; Binding Sites; Brain; Cations, Divalent; Humans; Metals; Oxidative Stress; Oxygen; Parkinson Disease; Phosphorylation; Protein Aggregation, Pathological; Protein Binding; Protein Domains; Protein Processing, Post-Translational; Structure-Activity Relationship; Sumoylation

Recent evidence has advanced our understanding of the function of sleep to include removal of neurotoxic protein aggregates via the glymphatic system. However, most research on the glymphatic system utilizes animal models, and the function of waste clearance processes in humans remains unclear. Understanding glymphatic function offers new insight into the development of neurodegenerative diseases that result from toxic protein inclusions, particularly those characterized by neuropathological sleep dysfunction, like Parkinson's disease (PD). In PD, we propose that glymphatic flow may be compromised due to the combined neurotoxic effects of alpha-synuclein protein aggregates and deteriorated dopaminergic neurons that are linked to altered REM sleep, circadian rhythms, and clock gene dysfunction. This review highlights the importance of understanding the functional role of glymphatic system disturbance in neurodegenerative disorders and the subsequent clinical and neuropathological effects on disease progression. Future research initiatives utilizing noninvasive brain imaging methods in human subjects with PD are warranted, as in vivo identification of functional biomarkers in glymphatic system functioning may improve clinical diagnosis and treatment of PD.

Topics: alpha-Synuclein; CLOCK Proteins; Glymphatic System; Humans; Parkinson Disease; Sleep Wake Disorders

α-Synuclein (α-syn) represents the main component of the amyloid aggregates present in Parkinson's disease and other neurodegenerative disorders, collectively named synucleinopathies. Although α-syn is considered a natively unfolded protein, it shows great structural flexibility which allows the protein to adopt highly rich beta-sheet structures like protofibrils, oligomers and fibrils. In addition, this protein can adopt alpha-helix rich structures when interacts with fatty acids or acidic phospholipid vesicle membranes. When analyzing the toxicity of α-syn, protein oligomers are thought to be the main neurotoxic species by mechanisms that involve modification of intracellular calcium levels, mitochondrial and lysosomal function. Extracellular fibrillar α-syn promotes intracellular protein aggregation and shows many toxic effects as well. Nitro-fatty acids (nitroalkenes) represent novel pleiotropic anti-inflammatory signaling mediators that could interact with α-syn to exert unraveling actions. Herein, we demonstrated that nitro-oleic acid (NO

Topics: alpha-Synuclein; Amyloid; Humans; Neurodegenerative Diseases; Oleic Acid; Parkinson Disease; Phospholipids

With the aging of population, neurological disorders, and especially disorders involving defects in protein conformation (also known as proteopathies) pose a serious socio-economic problem. So far there is no effective treatment for most proteopathies, including Parkinson's disease (PD). The mechanism underlying PD pathogenesis is largely unknown, and the hallmark proteins, α-synuclein (SYN) and tubulin polymerization promoting protein (TPPP/p25) are challenging drug targets. These proteins are intrinsically disordered with high conformational plasticity, and have diverse physiological and pathological functions. In the healthy brain, SYN and TPPP/p25 occur in neurons and oligodendrocytes, respectively; however, in PD and multiple system atrophy, they are co-enriched and co-localized in both cell types, thereby marking pathogenesis. Although large inclusions appear at a late disease stage, small, soluble assemblies of SYN promoted by TPPP/p25 are pathogenic. In the light of these issues, we established a new innovative strategy for the validation of a specific drug target based upon the identification of contact surfaces of the pathological SYN-TPPP/p25 complex that may lead to the development of peptidomimetic foldamers suitable for pharmaceutical intervention.

Topics: alpha-Synuclein; Drug Design; Humans; Molecular Targeted Therapy; Nerve Tissue Proteins; Parkinson Disease; Protein Conformation

The intracellular accumulation of misfolded alpha-synuclein pathology, termed Lewy pathology, throughout the brain is a phenomenon central to Parkinson's disease pathogenesis. In recent years it has become apparent that Lewy pathology can spread from neuron-to-neuron and between interconnected brain regions. Understanding the phenomenon of Lewy pathology propagation holds great promise in its explanatory power to determine the etiology of Parkinson's disease and related synucleinopathies. However, it remains to be seen if the spread of Lewy pathology is critical for driving this disease. Here we discuss the spreading of Lewy pathology while highlighting some important concepts and experimental observations. We conclude that further studies are required to determine if, and how, the spreading behavior of Lewy pathology is involved in Parkinson's disease. "This article is part of the Special Issue Synuclein".

Topics: alpha-Synuclein; Amyloid; Animals; Biopolymers; Brain; Disease Progression; Gene-Environment Interaction; Humans; Interneurons; Lewy Bodies; Mice; Mice, Transgenic; Models, Neurological; Neurons; Organ Specificity; Parkinson Disease; Prions; Protein Aggregates; Protein Transport; Recombinant Proteins

Accumulation of alpha-synuclein protein aggregates is the hallmark neuropathologic feature of synucleinopathies such as Parkinson's disease. Rare point mutations and multiplications in SNCA, the gene encoding alpha-synuclein, as well as other genetic alterations are linked to familial Parkinson's disease cases with high penetrance and hence constitute major genetic risk factors for Parkinson's disease. However, the preponderance of cases seems sporadic, most likely based on a complex interplay between genetic predispositions, aging processes and environmental influences. Deciphering the impact of these environmental factors and their interactions with the individual genetic background in humans is challenging and often requires large cohorts, complicated study designs, and longitudinal set-ups. In contrast, rodent models offer an ideal system to study the influence of individual environmental aspects under controlled genetic background and standardized conditions. In this review, we highlight findings from studies examining effects of environmental enrichment mimicking stimulation of the brain by its physical and social surroundings as well as of environmental stressors on brain health in the context of Parkinson's disease. We discuss possible internal molecular transducers of such environmental cues in Parkinson's disease rodent models and emphasize their potential in developing novel avenues to much-needed therapies for this still incurable disease. This article is part of the Special Issue "Synuclein".

Topics: alpha-Synuclein; Animals; Brain; Diseases in Twins; Epigenesis, Genetic; Gene-Environment Interaction; Humans; Lewy Bodies; Mice; Mice, Knockout; Motor Activity; Parkinson Disease; Parkinsonian Disorders; Pesticides; Physical Stimulation; Protein Aggregation, Pathological; Risk Factors; Stress, Physiological; Stress, Psychological; Synucleinopathies

Over 20 years ago, the synaptic protein α-synuclein was identified as the primary component of the Lewy bodies (LBs) that are a sine qua non of Parkinson's disease (PD). Since that time, extensive research has demonstrated that α-synuclein pathology is not only a hallmark of PD, but can also cause neuronal dysfunction and death. Detailed staging of α-synuclein pathology in the brains of patients has revealed a progressive pattern of pathology that correlates with the symptoms of disease. Early in the disease course, PD patients exhibit motor dysfunction, and α-synuclein pathology at this stage is primarily found in regions controlling motor function. At later stages of disease as patients' cognitive function deteriorates, α-synuclein pathology can be found in cortical structures responsible for higher cognitive processing. The stereotypical progression of α-synuclein pathology through the brain over time suggests that there may be a physical transmission of pathological α-synuclein from one area of the brain to another. The transmission hypothesis posits that an initial seed of pathological α-synuclein in one neuron may be released and taken up by another vulnerable neuron and thereby initiate pathological misfolding of α-synuclein in the recipient neuron. In recent years, convergent evidence from various studies has indicated that pathological protein transmission can occur in the human brain. Cell and animal models based on the transmission hypothesis have shown not only that pathological α-synuclein can be transmitted from cell-to-cell, but that this pathology can lead to neuronal dysfunction and degeneration. The α-synuclein transmission hypothesis has profound implications for treatment of what is currently an intractable neurodegenerative disease. In this review, we explore the evidence for cell-to-cell transmission of pathological α-synuclein, the current understanding of how pathological α-synuclein can move to a new cell and template misfolding, and the therapeutic implications of α-synuclein transmission.

Topics: alpha-Synuclein; Animals; Brain; Glymphatic System; Humans; Lewy Bodies; Parkinson Disease; Synucleinopathies

Parkinson's disease (PD) is a movement disorder, and its common characteristics include the loss of dopaminergic neurons and the accumulation of a special type of cytoplasmic inclusions called Lewy bodies in the substantia nigra pars compacta, which are more prevalent in the elderly. However, the pathophysiology of PD is still elusive. In this review, we summarized five common factors involved in PD, namely, (i) oxidative stress, (ii) mitochondrial dysfunction, (iii) inflammation, (iv) abnormal α-synuclein, and (v) endogenous neurotoxins, and proposed a hypothesis involving a damaging cycle. Oxidative stress-triggered aldehydes react with biogenic amines to produce endogenous neurotoxins. They cause mitochondrial dysfunction and the formation of inflammasomes, which induce the activation of neuroglial cells and the infiltration of T lymphocytes. The synergistic effect of these processes fosters chronic inflammation and α-synuclein aggregation and further exacerbates the impact of oxidative stress to establish a damaging cycle that eventually results in the degeneration of dopaminergic neurons. This damaging cycle provides an explanation of progressive neuronal death during the pathogenesis of PD and provides new potential targets beneficial for developing new drugs and approaches for clinical neuroprotection.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Aldehydes; alpha-Synuclein; Antiparkinson Agents; Biogenic Amines; Drug Design; Gene-Environment Interaction; Humans; Inflammasomes; MicroRNAs; Mitochondria; Models, Neurological; Mutation; Neuroglia; Oxidative Stress; Oxidopamine; Parkinson Disease; Protein Aggregation, Pathological; T-Lymphocyte Subsets

Alpha-synuclein positive-intracytoplasmic inclusions are the common denominators of the synucleinopathies present as Lewy bodies in Parkinson's disease, dementia with Lewy bodies, or glial cytoplasmic inclusions in multiple system atrophy. These neurodegenerative diseases also exhibit cellular dyshomeostasis, such as autophagy impairment. Several decades of research have questioned the potential link between the autophagy machinery and alpha-synuclein protein toxicity in synucleinopathy and neurodegenerative processes. Here, we aimed to discuss the active participation of autophagy impairment in alpha-synuclein accumulation and propagation, as well as alpha-synuclein-independent neurodegenerative processes in the field of synucleinopathy. Therapeutic approaches targeting the restoration of autophagy have started to emerge as relevant strategies to reverse pathological features in synucleinopathies.

Topics: alpha-Synuclein; Animals; Autophagy; Humans; Lysosomes; Mitophagy; Parkinson Disease; Synucleinopathies; TOR Serine-Threonine Kinases

After the first research declaring the generation of human induced pluripotent stem cells (hiPSCs) in 2007, several attempts have been made to model neurodegenerative disease in vitro during the past decade. Parkinson's disease (PD) is the second most common neurodegenerative disorder, which is mainly characterized by motor dysfunction. The formation of unique and filamentous inclusion bodies called Lewy bodies (LBs) is the hallmark of both PD and dementia with LBs. The key pathology in PD is generally considered to be the alpha-synuclein (α-syn) accumulation, although it is still controversial whether this protein aggregation is a cause or consequence of neurodegeneration. In the present work, the recently published researches which recapitulated the α-syn aggregation phenomena in sporadic and familial PD hiPSC models were reviewed. Furthermore, the advantages and potentials of using patient-derived PD hiPSC with focus on α-syn aggregation have been discussed. [BMB Reports 2019; 52(6): 349-359].

Topics: alpha-Synuclein; Humans; Induced Pluripotent Stem Cells; Lewy Bodies; Neurodegenerative Diseases; Parkinson Disease; Protein Aggregation, Pathological

Loss of dopaminergic neurons in the substantia nigra is one of the pathogenic hallmarks of Parkinson's disease, yet the underlying molecular mechanisms remain enigmatic. While aberrant redox metabolism strongly associated with iron dysregulation and accumulation of dysfunctional mitochondria is considered as one of the major contributors to neurodegeneration and death of dopaminergic cells, the specific anomalies in the molecular machinery and pathways leading to the PD development and progression have not been identified. The high efficiency and relative simplicity of a new genome editing tool, CRISPR/Cas9, make its applications attractive for deciphering molecular changes driving PD-related impairments of redox metabolism and lipid peroxidation in relation to mishandling of iron, aggregation and oligomerization of alpha-synuclein and mitochondrial injury as well as in mechanisms of mitophagy and programs of regulated cell death (apoptosis and ferroptosis). These insights into the mechanisms of PD pathology may be used for the identification of new targets for therapeutic interventions and innovative approaches to genome editing, including CRISPR/Cas9.

Topics: alpha-Synuclein; Cardiolipins; CRISPR-Associated Protein 9; CRISPR-Cas Systems; Dopaminergic Neurons; Ferroptosis; Gene Editing; Humans; Iron; Lipid Peroxidation; Mitochondria; Mitophagy; Mutation; Oxidation-Reduction; Parkinson Disease; Reactive Oxygen Species; Substantia Nigra

Since the landmark discovery that point mutations in the α-synuclein gene (SNCA) cause familial Parkinson's disease (PD) more than 2 decades ago, extensive research has been conducted to unravel the molecular and cellular mechanisms by which α-synuclein drives PD pathogenesis resulting in selective neurodegeneration of vulnerable neuronal populations. Current interest focuses on the identification of relevant toxic α-synuclein conformers and their interaction with basic cellular functions. In this context, seminal advances have been made in defining mechanisms of α-synuclein's toxicity in neurons, but many open questions remain regarding its neuronal subtype pathophysiology, as well as the defining the most disease relevant conformations. Moreover, we still only have a partial understanding of the full spectrum of α-synuclein's physiological functions both in neurons and in other cells. In this short review, we focus on cell-specific responses to α-synuclein with a focus on the toxic conformers of α-synuclein. We will not discuss more general cellular death pathways, which have been comprehensively covered by a number of elegant recent reviews.

Topics: alpha-Synuclein; Animals; Brain; Humans; Neurons; Oxidative Stress; Parkinson Disease; Point Mutation

Both iron deposition and α-synuclein aggregation are neuropathological hallmarks of Parkinson's disease (PD). We aimed to summarize the extensive interactions between these two factors. The direct structural links between iron and α-synuclein suggest that structural reorganization provokes α-synuclein conformational change. Iron post-transcriptionally regulates α-synuclein synthesis in the presence of iron-responsive element. Increased oxidative/nitrative stress induced by iron is believed to be involved in the post-translational modulation of α-synuclein. Iron modulates proteolytic pathways and therefore participates in the regulation of α-synuclein levels. Meanwhile, the recycling of iron through ferritin degradation suggests a link from the aspects of the degradation signaling pathway. Finally, α-synuclein might regulate iron metabolism through its ferrireductase activity. A prominent role of α-synuclein in iron homeostasis is involved in the uptake of transferrin-Fe. These findings suggest that intracellular iron and α-synuclein are closely related to each other, contributing to the vulnerability of dopaminergic neurons or even to a vicious cycle of toxicity in the pathology of PD.

Topics: alpha-Synuclein; Dopaminergic Neurons; Ferritins; FMN Reductase; Homeostasis; Humans; Iron; Oxidative Stress; Parkinson Disease; Signal Transduction; Transferrin

Parkinson's disease (PD) comprises a spectrum of disorders with differing subtypes, the vast majority of which share Lewy bodies (LB) as a characteristic pathological hallmark. The process(es) underlying LB generation and its causal trigger molecules are not yet fully understood. α-Synuclein (α-syn) is a major component of LB and SNCA gene missense mutations or duplications/triplications are causal for rare hereditary forms of PD. As typical sporadic PD is associated with LB pathology, a factor of major importance is the study of the α-syn protein and its pathology. α-Syn pathology is, however, also evident in multiple system atrophy (MSA) and Lewy body disease (LBD), making it non-specific for PD. In addition, there is an overlap of these α-synucleinopathies with other protein-misfolding diseases. It has been proven that α-syn, phosphorylated tau protein (pτ), amyloid beta (Aβ) and other proteins show synergistic effects in the underlying pathogenic mechanisms. Multiple cell death mechanisms can induce pathological protein-cascades, but this can also be a reverse process. This holds true for the early phases of the disease process and especially for the progression of PD. In conclusion, while rare SNCA gene mutations are causal for a minority of familial PD patients, in sporadic PD (where common SNCA polymorphisms are the most consistent genetic risk factor across populations worldwide, accounting for 95% of PD patients) α-syn pathology is an important feature. Conversely, with regard to the etiopathogenesis of α-synucleinopathies PD, MSA and LBD, α-syn is rather a bystander contributing to multiple neurodegenerative processes, which overlap in their composition and individual strength. Therapeutic developments aiming to impact on α-syn pathology should take this fact into consideration.

Topics: alpha-Synuclein; Animals; Humans; Parkinson Disease

Over the last two decades important achievements in research of Parkinson's disease led to the identification of specific pathways as well as histopathological fingerprints underlying the pathophysiology of the disease. This knowledge represents the basis for targeted disease-modifying treatment strategies. These treatment options target specific molecular defects in the causal chain or focus on the pathological α‑synuclein species and their propagation. This article highlights the most relevant treatment approaches that are currently being addressed in preliminary clinical trials.

Topics: alpha-Synuclein; Clinical Trials as Topic; Humans; Parkinson Disease; Precision Medicine

Parkinson's disease (PD) is a progressive neurological disorder associated with the loss of dopaminergic neurons (DNs) in the substantia nigra and the widespread accumulation of α-synuclein (α-syn) protein, leading to motor impairments and eventual cognitive dysfunction. In-vitro cell cultures and in-vivo animal models have provided the opportunity to investigate the PD pathological hallmarks and identify different therapeutic compounds. However, PD pathogenesis and causes are still not well understood, and effective inhibitory drugs for PD are yet to be discovered. Biologically simple but pathologically relevant disease models and advanced screening technologies are needed to reveal the mechanisms underpinning protein aggregation and PD progression. For instance, Caenorhabditis elegans (C. elegans) offers many advantages for fundamental PD neurobehavioral studies including a simple, well-mapped, and accessible neuronal system, genetic homology to humans, body transparency and amenability to genetic manipulation. Several transgenic worm strains that exhibit multiple PD-related phenotypes have been developed to perform neuronal and behavioral assays and drug screening. However, in conventional worm-based assays, the commonly used techniques are equipment-intensive, slow and low in throughput. Over the past two decades, microfluidics technology has contributed significantly to automation and control of C. elegans assays. In this review, we focus on C. elegans PD models and the recent advancements in microfluidic platforms used for manipulation, handling and neurobehavioral screening of these models. Moreover, we highlight the potential of C. elegans to elucidate the in-vivo mechanisms of neuron-to-neuron protein transfer that may underlie spreading Lewy pathology in PD, and its suitability for in-vitro studies. Given the advantages of C. elegans and microfluidics technology, their integration has the potential to facilitate the investigation of disease pathology and discovery of potential chemical leads for PD.

Topics: alpha-Synuclein; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Culture Techniques; Cognitive Dysfunction; Disease Models, Animal; Disease Progression; Dopaminergic Neurons; Drug Evaluation, Preclinical; Equipment Design; Genotype; Humans; Lab-On-A-Chip Devices; Materials Testing; Microfluidics; Parkinson Disease; Phenotype; Substantia Nigra

Neuronal microtubules are key determinants of cell morphology, differentiation, migration and polarity, and contribute to intracellular trafficking along axons and dendrites. Microtubules are strictly regulated and alterations in their dynamics can lead to catastrophic effects in the neuron. Indeed, the importance of the microtubule cytoskeleton in many human diseases is emerging. Remarkably, a growing body of evidence indicates that microtubule defects could be linked to Parkinson's disease pathogenesis. Only a few of the causes of the progressive neuronal loss underlying this disorder have been identified. They include gene mutations and toxin exposure, but the trigger leading to neurodegeneration is still unknown. In this scenario, the evidence showing that mutated proteins in Parkinson's disease are involved in the regulation of the microtubule cytoskeleton is intriguing. Here, we focus on α-Synuclein, Parkin and Leucine-rich repeat kinase 2 (LRRK2), the three main proteins linked to the familial forms of the disease. The aim is to dissect their interaction with tubulin and microtubules in both physiological and pathological conditions, in which these proteins are overexpressed, mutated or absent. We highlight the relevance of such an interaction and suggest that these proteins could trigger neurodegeneration via defective regulation of the microtubule cytoskeleton.

Topics: alpha-Synuclein; Animals; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Microtubules; Neurons; Parkinson Disease; Protein Binding; Ubiquitin-Protein Ligases

α-Synuclein (αS) is the major component of the filamentous inclusions that constitute the defining characteristic of neurodegenerative synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. αS is deposited in a hyperphosphorylated and ubiquitinated form with a β-sheet-rich fibrillar structure in diseased brains. In 2008, some researchers reported that embryonic neurons transplanted into Parkinson's disease brains had Lewy body-like pathologies, suggesting that pathological αS propagates from diseased neurons to young neurons. Subsequently, a growing body of evidence supported the cell-to-cell spread of αS pathologies. Recent studies have revealed that intracerebral injection of insoluble αS into wild-type mice can induce prion-like propagation of phosphorylated αS pathology even 1 month after injection, while injection into αS-knockout mice failed to induce any pathology. We also showed that intracerebral injection of insoluble αS into adult common marmoset brains results in the spreading of abundant αS pathology. These in vivo experiments clearly indicate that insoluble αS has prion-like properties and that it propagates through neural networks. The underlying mechanisms of αS propagation are still poorly understood, but αS propagation model animals could be helpful in elucidating the pathogenetic mechanisms and developing drugs for synucleinopathies.

Topics: alpha-Synuclein; Animals; Brain; Callithrix; Humans; Lewy Body Disease; Mice; Neurodegenerative Diseases; Parkinson Disease; Phosphorylation; Prions; Protein Aggregation, Pathological

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease and is estimated to affect approximately 1-4% of individuals aged over 60 years old. Although considerable efforts have been invested into developing disease-modifying therapies for Parkinson's disease, such efforts have been confounded by the difficulty in accurately diagnosing Parkinson's disease during life to enable accurate patient stratification for clinical trialling of candidate therapeutics. Therefore, the search for effective biomarkers that can be accurately evaluated during life with non-invasive means is a pressing issue in the field. Since the discovery of α-synuclein (α-syn) as a protein linked to a familial form of Parkinson's disease, later identified as the major protein component of the neuropathological hallmark of idiopathic Parkinson's disease, considerable interest has focused on this protein and its distinct conformers. We describe here the progress that has been made in the area of Parkinson's disease biomarker discovery with a focus on α-synuclein. In particular, we highlight the novel assays that have been employed and the increasing complexity in evaluating α-synuclein with regard to the considerable diversity of conformers that exist in the biofluids and peripheral tissues under disease conditions. "This article is part of the Special Issue Synuclein."

Topics: alpha-Synuclein; Biomarkers; Blotting, Western; Body Fluids; Brain; Cross-Sectional Studies; Disease Progression; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Gonads; Humans; Longitudinal Studies; Mass Spectrometry; Mucous Membrane; Organ Specificity; Parkinson Disease; Phosphorylation; Positron-Emission Tomography; Protein Aggregates; Protein Processing, Post-Translational; Salivary Glands; Skin

The protein α-synuclein has a central role in the pathogenesis of Parkinson's disease (PD). In this review, we discuss recent results concerning its primary function, which appears to be on cell membranes. The pre-synaptic location of synuclein has suggested a role in neurotransmitter release and it apparently associates with synaptic vesicles because of their high curvature. Indeed, synuclein over-expression inhibits synaptic vesicle exocytosis. However, loss of synuclein has not yet been shown to have a major effect on synaptic transmission. Consistent with work showing that synuclein can promote as well as sense membrane curvature, recent analysis of synuclein triple knockout mice now shows that synuclein accelerates dilation of the exocytic fusion pore. This form of regulation affects primarily the release of slowly discharged lumenal cargo such as neural peptides, but presumably also contributes to maintenance of the release site. This article is part of the Special Issue "Synuclein".

Topics: alpha-Synuclein; Animals; Axons; Cell Membrane; Disease Models, Animal; Dopamine; Exocytosis; Humans; Membrane Fusion; Mice, Knockout; Mice, Transgenic; Mitochondria; Mutation, Missense; Parkinson Disease; Presynaptic Terminals; Protein Domains; Protein Folding; Protein Isoforms; Recombinant Proteins; Secretory Vesicles; Synaptic Vesicles

Toll-like receptors (TLRs) are pattern recognition receptors which mediate an inflammatory response upon the detection of specific molecular patterns found on foreign organisms and on endogenous damage-related molecules. These receptors play a major role in the activation of microglia, the innate immune cells of the CNS, and are also expressed in peripheral tissues, including blood mononuclear cells and the gut. It is well established that immune activation, in both the brain and periphery, is a feature of Parkinson's disease as well as other α-synucleinopathies. Aggregated forms of α-synuclein can act as ligands for TLRs (particularly TLR2 and TLR4), and hence these receptors may play a critical role in mediating a detrimental immune response to this protein, as well as other inflammatory signals in Parkinson's and related α-synucleinopathies. In this review, the potential role of TLRs in contributing to the progression of these disorders is discussed. Existing evidence comes predominantly from studies in in vitro and in vivo models, as well as analyses of postmortem human brain tissue and pre-clinical studies of TLR inhibitors. This evidence is evaluated in detail, and the potential for therapeutic intervention in α-synucleinopathies through TLR inhibition is discussed.

Topics: alpha-Synuclein; Animals; Brain; Humans; Microglia; Parkinson Disease; Parkinsonian Disorders; Synucleinopathies; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors

Homozygous and heterozygous mutations in GBA1, the gene implicated in Gaucher disease, increase the risk and severity of Parkinson disease (PD). We evaluated the design, phenotype, strengths, and limitations of current GBA1-associated PD mouse models. Although faithful modeling of a genetic risk factor poses many challenges, the different approaches taken were successful in revealing predisposing abnormalities in heterozygotes for GBA1 mutations and demonstrating the deleterious effects of GBA1 impairment on the PD course in PD models. GBA1-PD models differ in key parameters, with no single model recapitulating all aspects of the GBA1-PD puzzle, emphasizing the importance of selecting the proper in vivo model depending on the specific molecular mechanism or potential therapy being studied.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Gaucher Disease; Glucosylceramidase; Humans; Mutation; Parkinson Disease

Previous studies that have investigated the potential of in vivo abnormal α-synuclein deposits as a pathological biomarker for PD included few participants and reported different diagnostic accuracies. Here, we aimed to confirm the diagnostic value of in vivo α-synuclein deposits in PD through a systematic review and meta-analysis, with special emphasis on determining the tissue most suitable for examination and assessing whether anti-native α-synuclein or anti-phosphorylated α-synuclein antibodies should be used. Databases were searched on December 30, 2018. We finally included 41 case-control studies that examined in vivo tissue samples using anti-native α-synuclein or anti-phosphorylated α-synuclein antibody in PD patients and controls. Using a univariate random-effects model, pooled sensitivity and specificity (95% confidence interval) of anti-native α-synuclein antibody were 0.54 (0.49-0.60) and 0.72 (0.68-0.76) for the gastrointestinal tract and 0.76 (0.60-0.89) and 0.60 (0.43-0.74) for the skin. Pooled sensitivity and specificity (95% confidence interval) of anti-phosphorylated α-synuclein antibody were 0.43 (0.37-0.48) and 0.82 (0.78-0.86) for the gastrointestinal tract, 0.76 (0.69-0.82) and 1.00 (0.98-1.00) for the skin, 0.42 (0.26-0.59) and 0.94 (0.84-0.99) for the minor salivary glands, and 0.66 (0.51-0.79) and 0.96 (0.86-1.00) for the submandibular glands. Although ubiquitous heterogeneity between the included studies should be noted when interpreting our results, our analyses demonstrated the following: (1) in vivo α-synuclein immunoreactivity has the potential as a pathological biomarker for PD; (2) anti-phosphorylated α-synuclein antibody consistently has higher specificity than anti-native α-synuclein antibody; and (3) skin biopsy examination using anti-phosphorylated α-synuclein antibody has the best diagnostic accuracy, although feasibility remains an important issue. © 2019 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Biomarkers; Brain; Gastrointestinal Tract; Humans; Parkinson Disease; Submandibular Gland

Numerous case-control studies have investigated the relationship between rs356219 and rs3822086 polymorphisms and Parkinson's disease (PD) susceptibility. However, these publications have obtained contradictory results. In this study, we conducted a meta-analysis to evaluate the possible association between the two polymorphisms and PD. Literature searches were conducted on PubMed, Web of Science, EMBASE, CNKI and the Wanfang database on studies published until March 2019. Authentic data were calculated utilizing STATA 12.0 statistics software on the data provided in each study. The genetic association between SNCA polymorphisms and the risk of PD was evaluated using the pooled odds ratios (OR) and 95% confidence interval (CI). The results indicate that there is a significant association between rs356219 polymorphism and PD susceptibility for all genetic models (allelic: OR = 1.377, 95% CI: 1.275-1.487, p = 0.000; homozygous: OR = 1.958, 95% CI: 1.666-2.301, p = 0.000; heterozygous: OR = 1.261, 95% CI: 1.158-1.373, p = 0.000; dominant: OR = 1.431, 95% CI: 1.320-1.550, p = 0.000; recessive: OR = 1.632, 95% CI: 1.431-1.861, p = 0.000), which is consistent with the results of the subgroup analyses on Asians and Caucasians. In addition, rs3822086 polymorphism was found to be related to PD in the allelic (OR = 1.249, 95% CI: 1.099-1.419, p = 0.001), homozygous (OR = 1.479, 95% CI: 1.142-1.915, p = 0.003), heterozygous (OR = 1.292, 95% CI: 1.033-1.615, p = 0.025) and dominant (OR = 1.331, 95% CI: 1.030-1.719, p = 0.029) models. Therefore, our results suggest that the presence of SNCA rs356219 and rs3822086 variants may increase the risk of PD.

Topics: alpha-Synuclein; Case-Control Studies; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Humans; Parkinson Disease; Polymorphism, Single Nucleotide

This article describes pathogenic concepts and factors, in particular glycolipid abnormalities, that create cell dysfunction and synaptic loss in neurodegenerative diseases. By phenocopying lysosomal storage disorders, such as Gaucher disease and related disorders, age- and dose-dependent changes in glycolipid cell metabolism can lead to Parkinson's disease and related dementias. Recent results show that perturbation of sphingolipid metabolism can precede or is a part of abnormal protein handling in both genetic and idiopathic Parkinson's disease and Lewy body dementia. In aging and genetic predisposition with lipid disturbance, α-synuclein's normal vesicular and synaptic role may be detrimentally shifted toward accommodating and binding such lipids. Specific neuronal glycolipid, protein, and vesicular interactions create potential pathophysiology that is amplified by astroglial and microglial immune mechanisms resulting in neurodegeneration. This perspective provides a new logic for therapeutic interventions that do not focus on protein aggregation, but rather provides a guide to the complex biology and the common sequence of events that lead to age-dependent neurodegenerative disorders.

Topics: alpha-Synuclein; Animals; Brain; Humans; Inflammation; Nerve Degeneration; Neurons; Parkinson Disease; tau Proteins

Alpha-synuclein (αS) is the major constituent of Lewy bodies and a pathogenic hallmark of all synucleinopathathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). All diseases are determined by αS aggregate deposition but can be separated into distinct pathological phenotypes and diagnostic criteria. Here we attempt to reinterpret the literature, particularly in terms of how αS structure may relate to pathology. We do so in the context of a rapidly evolving field, taking into account newly revealed structural information on both native and pathogenic forms of the αS protein, including recent solid state NMR and cryoEM fibril structures. We discuss how these new findings impact on current understanding of αS and PD, and where this information may direct the field.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It is characterized by a slow and progressive loss of dopaminergic neurons. Its neuropathological hallmark is the accumulation of aggregated form of α-synuclein (α-syn) protein in intracellular inclusions known as Lewy bodies. This aggregated α-syn is believed to be central to the pathogenesis of PD. Emerging evidence suggests that aggregated forms of α-syn self-amplificates and propagates spreading from cell-to-cell in a "prion-like" fashion. Genetics and environmental factors are known causes for the pathogenesis of PD. In last years, inflammation in the pathophysiology of PD is gaining more importance. This neuroinflammation seems to contribute to the progressive degeneration of dopaminergic neurons. The currently available therapies for PD fail to modify the disease progression and neurodegeneration. The connection between α-syn and PD makes α-syn the major therapeutic target. We summarize the possible therapeutic strategies to target α-syn according to the steps in the molecular pathogenesis. The contribution of neuroinflammation to the progression of the disease and the "prion-like" hypothesis which enables targeting the extracellular phase of transmission of α-syn, make immunotherapy probably the most promising therapeutic approach for PD.

Topics: alpha-Synuclein; Animals; Drugs, Investigational; Humans; Immunotherapy; Molecular Targeted Therapy; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and is characterized for being an idiopathic and multifactorial disease. Extensive research has been conducted to explain the origin of the disease, but it still remains elusive. It is well known that dopamine oxidation, through the endogenous formation of toxic metabolites, is a key process in the activation of a cascade of molecular events that leads to cellular death in the hallmark of PD. Thio-catecholamines, such as 5-S-cysteinyl-dopamine, 5-S-glutathionyl-dopamine and derived benzothiazines, are endogenous metabolites formed in the dopamine oxidative degradation pathway. Those metabolites have been shown to be highly toxic to neurons in the substantia nigra pars compacta, activating molecular mechanisms that ultimately lead to neuronal death. In this review we describe the origin, formation and the toxic effects of 5-S-cysteinyl-dopamine and its oxidative derivatives that cause death to dopaminergic neurons. Furthermore, we correlate the formation of those metabolites with the neurodegeneration progress in PD. In addition, we present the reported neuroprotective strategies of products that protect against the cellular damage of those thio-catecholamines. Finally, we discuss the advantages in the use of 5-S-cysteinyl-dopamine as a potential biomarker for PD.

Topics: alpha-Synuclein; Biomarkers; Dopamine; Dopaminergic Neurons; Endoplasmic Reticulum Stress; Humans; Metabolic Networks and Pathways; Mitochondria; Nerve Tissue Proteins; Neuroprotective Agents; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pars Compacta; Sulfur

Of the documented cases of Parkinson's disease (PD), about 10% have a genetic background. The remaining cases of PD have unknown etiology. Thus, environmental factors appear to play a pathogenic role in most of the PD cases. Several of the so far known PD inducing chemicals appear to increase the formation of mitochondrial reactive oxygen species (ROS). A suspected environmental factor is the non-proteinogenic amino acid β-methylamino-l-alanine (BMAA), which may act to carry iron species into the brain and disrupt correct biosynthesis of proteins. In addition, in epidemiological studies, it has been reported a connection between PD and metal exposures, including iron, mercury, manganese, and lead. Research has shown elevated iron levels in the substantia nigra of PD patients. Mitochondrial dysfunction induced by genetic or environmental factors appears to evoke cascades of biochemical events, which include non-physiological leakage of ROS and arrest of the sensitive production of dopamine. A combination of increased ROS and loosely chelated iron causes neurotransmitter dysfunction. Recent research indicates that treatment with exogenous chelators, such as deferiprone, apomorphine, and hinokitiol, can inhibit PD progression. The endogenous chelator, neuromelanin, also appears to exert protection. In the present review, the pathogenic mechanisms and genetic susceptibilities to metals in PD are explored. The paper is also focused on strategies for the therapy of PD, mainly by using chelation therapy to reduce the level of iron.

Topics: alpha-Synuclein; Animals; Dopamine; Glutathione; Humans; Iron; Metals; Oxidative Stress; Parkinson Disease; Reactive Oxygen Species; Substantia Nigra; Synaptic Transmission

In recent years, the diagnostic approach to rapid eye movement (REM) sleep behavior disorder (RBD) has become more objective and accurate. This was achieved mainly by introduction of methods to exactly quantify electromyographic (EMG) activity in various muscles during REM sleep. The most established muscle combination for RBD diagnosis is the mentalis and upper extremity EMG. Computer-assisted systems for this analysis have been described, and an increasing number of studies looked into analysis of video events. Recently, prodromal phases of isolated RBD have been recognized.

Topics: alpha-Synuclein; Disease Progression; Electromyography; Humans; Image Processing, Computer-Assisted; Intestinal Mucosa; Lewy Body Disease; Parkinson Disease; Polysomnography; Precision Medicine; Prodromal Symptoms; REM Sleep Behavior Disorder; Salivary Glands; Skin; Sleep, REM; Synucleinopathies; Video Recording

Parkinson's disease (PD) is the second-most common neurodegenerative disorder, neuropathologically characterized by the aggregation of misfolded α-synuclein (α-syn) protein, which appears to be central to the onset and progression of PD pathology. Evidence from pioneering studies has highly advocated the existence of impaired autophagy pathways in the brains of PD patients. Autophagy is an evolutionarily conserved, homeostatic mechanism for minimizing abnormal protein aggregates and facilitating organelle turnover. Any aberration in constitutive autophagy activity results in the aggregation of misfolded α-syn, which, in turn, may further inhibit their own degradation-leading to a vicious cycle of neuronal death. Despite the plethora of available literature, there are still lacunas existing in our understanding of the exact cellular interplay between autophagy impairment and α-syn accumulation-mediated neurotoxicity. In this context, clearance of aggregated α-syn via up-regulation of the autophagy-lysosomal pathway could provide a pharmacologically viable approach to the treatment of PD. The present Review highlights the basics of autophagy and detrimental cross-talk between α-syn and chaperone-mediated autophagy, and α-syn and macroautophagy. It also depicts the interaction between α-syn and novel targets, LRRK2 and mTOR, followed by the role of autophagy in PD from a therapeutic perspective. More importantly, it further updates the reader's understanding of various newer therapeutic avenues that may accomplish disease modification via promoting clearance of toxic α-syn through activation of autophagy.

Topics: alpha-Synuclein; Animals; Autophagy; Humans; Lysosomes; Parkinson Disease

Research with animal models has led to critical health advances that have saved or improved the lives of millions of human beings. Specifically, nonhuman primate's genetic and anatomo-physiological similarities to humans are especially important for understanding processes like Parkinson's disease, which only occur in humans. Unambiguously, the unique contribution made by nonhuman primate research to our understanding of Parkinson's disease is widely recognized. For example, monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonisms are responsive to dopamine replacement therapies, mimicking what is seen in PD patients. Moreover, groundbreaking neuroanatomical and electrophysiological studies using this monkey model in the 1980s and 1990s enabled researchers to identify the neuronal circuits responsible for the cardinal motor features of PD. This led to the development of subthalamic surgical ablation and deep brain stimulation, the current therapeutic gold standard for neurosurgical treatment. More recently, the mechanisms of α-synuclein spreading testing the prion hypothesis for PD have yielded exciting results. In this review, we discuss and highlight how the findings from nonhuman primate research contribute to our understanding of idiopathic Parkinson's disease.

Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Parkinson Disease; Parkinson Disease, Secondary

Parkinson's disease (PD) is a complex, chronic and progressive neurodegenerative disease. While the etiology of PD is likely multifactorial, the protein α-synuclein is a central component to the pathogenesis of the disease. However, the mechanism by which α-synuclein causes toxicity and contributes to neuronal death remains unclear. Mitochondrial dysfunction is also widely considered to play a major role in the underlying mechanisms contributing to neurodegeneration in PD. This review discusses evidence for the neuropathological role for α-synuclein in the dysfunction of dopamine neurons in PD. We also discuss insights into the structure, localization, and cellular roles for α-synuclein that may influence its aggregation properties, ultimately impacting its pathogenicity, role in lysosomal dysfunction and activation of the neuroimmune response. We further highlight recent evidence linking α-synuclein and mitochondrial dysfunction in neurodegeneration. Identifying the underlying mechanisms responsible for this bi-directional relationship between α-synuclein and mitochondrial dysfunction may provide new insights into the pathophysiology of PD.

Topics: alpha-Synuclein; Animals; Humans; Inflammation; Mitochondria; Mitochondrial Diseases; Parkinson Disease

Proper understanding of the mechanism(s) by which α-synuclein misfolds and propagates may hold the key to unraveling the complex pathophysiology of Parkinson's disease. A more complete understanding of the disease itself, as well as establishing animal models that fully recapitulate pathological and functional disease progression, are needed to develop treatments that will delay, halt or reverse the disease course. Traditional neurotoxin-based animal models fail to mimic crucial aspects of Parkinson's and thus are not relevant for the study of neuroprotection and disease-modifying therapies. Therefore, a new era of animal models centered on α-synuclein has emerged with the utility of nonhuman primates in these studies beginning to become important. Indeed, disease modeling in nonhuman primates offers a more similar anatomical and genetic background to humans, and the ability to assess complex behavioral impairments that are difficult to test in rodents. Furthermore, results obtained from monkey studies translate better to applications in humans. In this review, we highlight the importance of α-synuclein in Parkinson's disease and discuss the development of α-synuclein based nonhuman primate models.

Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Parkinson Disease; Primates

It took almost 100 years before a meaningful advance occurred in any basic science understanding of Parkinson disease (PD) following James Parkinson's description in 1817. The Lewy body was described in 1912, and the substantia nigra was found to be depigmented with neuronal loss and gliosis in 1919. The link between dopamine and PD began in 1957, 140 years after Parkinson's Essay. Arvid Carlsson and Oleh Hornykiewicz were the major pioneers. The revolutionary therapeutic breakthrough was the introduction of high dosage levodopa therapy by George Cotzias in 1967. Following 40 years of the dopa/dopamine era, we have entered the era of alpha-synuclein, the protein present in Lewy bodies. Heiko Braak found that alpha-synuclein accumulates initially in the olfactory system and lower brainstem and then travels in an anatomic pattern to involve other regions of the brain and thereby cause progressive symptoms. Alpha-synuclein was somehow converted to a rogue protein. Where this originates and how it is propagated are under intense investigation. At the same time that the alpha-synuclein era was developing, clinical advances took place by recognizing PD as hosting a wide variety of nonmotor features with eventual cognitive impairment in many. Therapeutics has also evolved. Although the most effective therapy for the motor features remains levodopa, surgical approaches and drugs for nonmotor problems continue to expand our ability to treat people with PD. We can expect therapeutic advances in neuroprotection as the basic science discoveries uncovered in the alpha-synuclein era are translated into effective treatments.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Dopamine Agents; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Parkinson Disease

Parkinson's disease (PD) is a multisystem disorder with involvement of the peripheral nervous system. Misfolding and aggregation of α-synuclein is central to the pathogenesis of PD, and it has been postulated that the disease may originate in olfactory and gastrointestinal nerve terminals. The prion-like behavior of α-synuclein has been convincingly demonstrated in vitro and in animal models of PD. Lewy-type pathology have been detected in peripheral organs many years prior to PD diagnosis, and 2 independent studies have now suggested that truncal vagotomy may be protective against the disorder. Other lines of evidence are difficult to reconcile with a peripheral onset of PD, most importantly the relative scarcity of post mortem cases with isolated gastrointestinal α-synuclein pathology without concomitant CNS pathology. This Scientific Perspectives article revisits some important topics with implications for the dual-hit hypothesis. An account of the neuroanatomical pathways necessary for stereotypical α-synuclein spreading is presented. Parallels to the existing knowledge on true prion disorders, including Creutzfeld-Jakob disease, are examined. Finally, the vagotomy studies and the somewhat inconsistent findings in the growing literature on peripheral α-synuclein pathology are discussed. It is concluded that the dual-hit hypothesis remains a potential explanation for PD pathogenesis, but several issues need to be resolved before more firm conclusions can be drawn. © 2017 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Animals; Central Nervous System; Humans; Neural Pathways; Parkinson Disease; Prions

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized pathologically by the presence of Lewy bodies comprised of insoluble alpha (α)-synuclein. Pathological, clinical and genetic studies demonstrate that mutations in the GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase) that is deficient in Gaucher's disease, are important risk factors for the development of PD. The molecular mechanism for the association between these two diseases is not completely understood. We discuss several possible mechanisms that may lead to GBA1-related neuronal death and α-synuclein accumulation including disruptions in lipid metabolism, protein trafficking and impaired protein quality control mechanisms. Elucidating the mechanism between GCase and α-synuclein may provide insight into potential therapeutic pathways for PD and related synucleinopathies.

Topics: alpha-Synuclein; Animals; Glucosylceramidase; Humans; Lysosomes; Models, Biological; Mutation; Parkinson Disease

Studies in the last decade have suggested the association of both neuroinflammatory processes and immune responses in Parkinson disease (PD) pathology. PD pathology is related to depleted dopamine levels, α-synuclein aggregation, and death of nigrostriatal dopaminergic neurons. Reports have suggested central and peripheral inflammation in the prodromal stage of the disease, which is sustained during disease progression. Alongside the activation of peripheral immune system exacerbates the dissonant central inflammatory responses and could contribute in synergistic neurodegeneration. Activated glial cells contribute significantly in the neuroinflammatory process during the occurrence of the disease and are also acknowledged as a hallmark of disease progression. However, the contribution of glial cells is not well defined in the context of neurodegeneration and neuroprotection. This review provides an overview of the roles of immune and inflammatory responses and their consequences in PD disease pathogenesis and also discusses possible therapeutic strategies for PD based on these findings.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Humans; Immune System; Inflammation; Microglia; Neuroglia; Parkinson Disease; Substantia Nigra

α-Synuclein (αS) is a neuronal protein that localises predominantly at the presynaptic terminals, and whose fibrillar aggregates are the major constituents of Lewy bodies in Parkinson's disease. In vivo αS is partitioned between water-soluble and membrane-bound states, and this highly regulated equilibrium influences its biological behaviour under both physiological and pathological conditions. Here we discuss the sequence and structural determinants underlying the transition between the unstructured cytosolic and partially structured membrane-bound states of αS. The balance between order and disorder in this protein system is crucial for the overall regulation of the membrane affinity, the ability to induce the clustering of synaptic vesicles, and the tendency to self assemble into amyloid fibrils at the surface of biological membranes.

Topics: alpha-Synuclein; Amino Acids; Amyloid; Cell Membrane; Cytosol; Humans; Kinetics; Lewy Bodies; Magnetic Resonance Spectroscopy; Neurons; Parkinson Disease; Protein Aggregates; Protein Binding; Solubility; Synaptic Vesicles; Thermodynamics

Parkinson's disease (PD) is a complex and heterogeneous neurological condition characterised mainly by bradykinesia, resting tremor, rigidity and postural instability, symptoms that together comprise the parkinsonian syndrome. Non-motor symptoms preceding and following clinical onset are also helpful diagnostic markers revealing a widespread and progressive pathology. Many other neurological conditions also include parkinsonism as primary or secondary symptom, confounding their diagnosis and treatment. Although overall disease course and end-stage pathological examination single out these conditions, the significant overlaps suggest that they are part of a continuous disease spectrum. Recent genetic discoveries support this idea because mutations in a few genes (α-synuclein,

Topics: alpha-Synuclein; Dopamine; Genes, Dominant; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mitochondria; Mutation; Neurons; Parkinson Disease; Parkinsonian Disorders; tau Proteins

Genetic background accounts for only 5 to 10% of the reported cases of Parkinson's disease (PD), while the remaining cases are of unknown etiology. It is believed that environmental factors may be involved in the causality of a large proportion of PD cases. Several PD genes are activated by xenobiotic exposure, and a link between pesticide exposure and PD has been demonstrated. Many epidemiological studies have shown an association between PD and exposure to metals such as mercury, lead, manganese, copper, iron, aluminum, bismuth, thallium, and zinc. This review explores the biological effects, the pathogenetic processes, genetic susceptibilities to metals as well as examining future strategies for PD treatment, such as chelation therapy.

Topics: alpha-Synuclein; Amyloidogenic Proteins; Chelation Therapy; Dopaminergic Neurons; Drug Synergism; Glutamic Acid; Glutathione; Glutathione Peroxidase; Humans; Metals, Heavy; Oxidative Stress; Parkinson Disease; Selenoproteins

There is a growing body of evidence in animal and cell based models of Parkinson's disease (PD) to suggest that overexpression and / or abnormal accumulation and aggregation of α-synuclein can trigger neuronal death. This important role of α-synuclein in PD pathogenesis is supported by the fact that duplication, triplication and mutations of α-synuclein gene cause familial forms of PD.. A review of literature was performed by searching PubMed and Google Scholar for relevant articles highlighting the pathogenic role of α-synuclein and the potential therapeutic implications of targeting various pathways related to this protein.. The overexpression and accumulation of α-synuclein within neurons may involve both transcriptional and post-transcriptional mechanisms including a decreased degradation of the protein through proteasomal or autophagic processes. The mechanisms of monomeric α-synuclein aggregating to oligomers and fibrils have been investigated intensively, but it is still not certain which form of this natively unfolded protein is responsible for toxicity. Likewise the proteotoxic pathways induced by α- synuclein leading to neuronal death are not elucidated completely but mitochondrial dysfunction, endoplasmic reticulum (ER) stress and altered ER-golgi transport may play crucial roles in this process. At the molecular level, the ability of α-synuclein to form pores in biomembranes or to interact with specific proteins of the cell organelles and the cytosol could be determining factors in the toxicity of this protein.. Despite many limitations in our present knowledge of physiological and pathological functions of α-synuclein, it appears that this protein may be a target for the development of neuroprotective drugs against PD. This review has discussed many such potential drugs which prevent the expression, accumulation and aggregation of α-synuclein or its interactions with mitochondria or ER and thereby effectively abolish α-synuclein mediated toxicity in different experimental models.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Humans; Neuroprotective Agents; Parkinson Disease

α-synuclein (αSyn) still remains a mysterious protein even two decades after SNCA encoding it was identified as the first causative gene of familial Parkinson's disease (PD). Accumulation of αSyn causes α-synucleinopathies including PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Recent advances in therapeutic approaches offer new antibody-, vaccine-, antisense-oligonucleotide- and small molecule-based options to reduce αSyn protein levels and aggregates in patient's brain. Gathering research information of other neurological disease particularly Alzheimer's disease, recent disappointment of an experimental amyloid plaques busting antibody in clinical trials underscores the difficulty of treating people who show even mild dementia as damage in their brain may already be too extensive. Prodromal intervention to inhibit the accumulation of pathogenic protein may advantageously provide a better outcome. However, treatment prior to onset is not ethically justified as standard practice at present. In this review, we initiate a refined concept to define early pathogenic state of αSyn accumulation before occurrence of brain damage as a disease criterion for αSyn dysregulation disease.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Brain; Gene Expression; Humans; Lewy Body Disease; Parkinson Disease

Alpha-synuclein (αSyn) plays a central role in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In sporadic PD and DLB, normally harmless αSyn proteins without any mutations might gain toxic functions by unknown mechanisms. Thus, it is important to elucidate the factors promoting the toxic conversion of αSyn, towards understanding the pathogenesis of and developing disease-modifying therapies for PD and DLB. Accumulating biophysical and biochemical studies have demonstrated that αSyn interacts with lipid membrane, and the interaction influences αSyn oligomerization and aggregation. Furthermore, genetic and clinicopathological studies have revealed mutations in the glucocerebrosidase 1 (GBA1) gene, which encodes a degrading enzyme for the glycolipid glucosylceramide (GlcCer), as strong risk factors for PD and DLB, and we recently demonstrated that GlcCer promotes toxic conversion of αSyn. Moreover, pathological studies have shown the existence of αSyn pathology in lysosomal storage disorders (LSDs) patient' brain, in which glycosphingolipids (GSLs) is found to be accumulated. In this review, we focus on the lipids as a key factor for inducing wild-type (WT) αSyn toxic conversion, we summarize the knowledge about the interaction between αSyn and lipid membrane, and propose our hypothesis that aberrantly accumulated GSLs might contribute to the toxic conversion of αSyn. Identifying the trigger for toxic conversion of αSyn would open a new therapeutic road to attenuate or prevent crucial events leading to the formation of toxic αSyn.

Topics: alpha-Synuclein; Animals; Brain; Glucosylceramidase; Humans; Lipids; Neurons; Parkinson Disease

Parkinson's disease (PD) is a debilitating neurodegenerative condition associated with tremor, rigidity, dementia, and gastrointestinal symptoms such as constipation, nausea and vomiting. The pathological hallmarks of PD are Lewy bodies and neurites in the brain and peripheral nerves. The major constituent of Lewy bodies is the neuronal protein α-synuclein. Misfolding of α-synuclein confers prion-like properties enabling its spread from cell to cell. Misfolded α-synuclein also serves as a template and induces misfolding of endogenous α-synuclein in recipient cells leading to the formation of oligomers that progress to fibrils and eventually Lewy bodies. Accumulating evidence suggests that PD may arise in the gut. Clinically, gastrointestinal symptoms often appear in patients before other neurological signs and aggregates of α-synuclein have been found in enteric nerves of PD patients. Importantly, patients undergoing vagotomy have a reduced risk of developing PD. Experimentally, abnormal forms of α-synuclein appear in enteric nerves before they appear in the brain and injection of abnormal α-synuclein into the wall of the intestine spreads to the vagus nerve. Ingested toxins and alterations in gut microbiota can induce α-synuclein aggregation and PD, however, it is not known how PD starts. Recently, it has been shown that sensory cells of the gut known as enteroendocrine cells (EECs) contain α-synuclein and synapse with enteric nerves, thus providing a connection from the gut to the brain. It is possible that abnormal α-synuclein first develops in EECs and spreads to the nervous system.

Topics: alpha-Synuclein; Animals; Enteroendocrine Cells; Gastrointestinal Tract; Humans; Lewy Bodies; Neurons; Parkinson Disease; Prions; Proteostasis Deficiencies

Amyloid-β and α-synuclein are intrinsically disordered proteins (IDPs), which are at the center of Alzheimer's and Parkinson's disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid-β and α-synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer's and Parkinson's diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-β and α-synuclein in relation to the pathologies of Alzheimer's and Parkinson's diseases. Furthermore, there are several natural genetic variations that play a role in the pathogenesis of familial cases of Alzheimer's and Parkinson's diseases, which are related to specific genetic defects inherited in dominant or recessive patterns. The present review summarizes the current understanding of monomeric and oligomeric forms of amyloid-β and α-synuclein, as well as the impacts of artificial and pathological missense mutations on the structural ensembles of these IDPs using molecular dynamics simulations. We also emphasize the recent investigations on residual secondary structure formation in dynamic conformational ensembles of amyloid-β and α-synuclein, such as β-structure linked to the oligomerization and fibrillation mechanisms related to the pathologies of Alzheimer's and Parkinson's diseases. This information represents an important foundation for the successful and efficient drug design studies.

Topics: Alleles; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Intrinsically Disordered Proteins; Molecular Dynamics Simulation; Mutation, Missense; Parkinson Disease; Protein Aggregates; Protein Aggregation, Pathological; Protein Binding; Protein Conformation; Protein Multimerization; Structure-Activity Relationship

Parkinson disease (PD) is a complex neurodegenerative disease characterised by multiple motor and non-motor symptoms. In the last 20 years, more than 20 genes have been identified as causes of parkinsonism. Following the observation of higher risk of PD in patients affected by Gaucher disease, a lysosomal disorder caused by mutations in the glucocerebrosidase (GBA) gene, it was discovered that mutations in this gene constitute the single largest risk factor for development of idiopathic PD. Patients with PD and GBA mutations are clinically indistinguishable from patients with idiopathic PD, although some characteristics emerge depending on the specific mutation, such as slightly earlier onset. The molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are multiple and not yet fully elucidated, they include alpha-synuclein aggregation, lysosomal-autophagy dysfunction and endoplasmic reticulum stress. Moreover, dysfunction of glucocerebrosidase has also been demonstrated in non-GBA PD, suggesting its interaction with other pathogenic mechanisms. Therefore, GBA enzyme function represents an interesting pharmacological target for PD. Cell and animal models suggest that increasing GBA enzyme activity can reduce alpha-synuclein levels. Clinical trials of ambroxol, a glucocerebrosidase chaperone, are currently ongoing in PD and PD dementia, as is a trial of substrate reduction therapy. The aim of this review is to summarise the main features of GBA-PD and discuss the implications of glucocerebrosidase modulation on PD pathogenesis.

Topics: alpha-Synuclein; Glucosylceramidase; Humans; Mutation; Parkinson Disease

Preclinical research on Parkinson's disease has relied heavily on mouse and rat animal models. Initially, PD animal models were generated primarily by chemical neurotoxins that induce acute loss of dopaminergic neurons in the substantia nigra. On the discovery of genetic mutations causally linked to PD, mice were used more than rats to generate laboratory animals bearing PD-linked mutations because mutagenesis was more difficult in rats. Recent advances in technology for mammalian genome engineering and optimization of viral expression vectors have increased the use of genetic rat models of PD. Emerging research tools include "knockout" rats with disruption of genes in which mutations have been causally linked to PD, including LRRK2, α-synuclein, Parkin, PINK1, and DJ-1. Rats have also been increasingly used for transgenic and viral-mediated overexpression of genes relevant to PD, particularly α-synuclein. It may not be realistic to obtain a single animal model that completely reproduces every feature of a human disease as complex as PD. Nevertheless, compared with mice with the same mutations, many genetic rat animal models of PD better reproduce key aspects of PD including progressive loss of dopaminergic neurons in the substantia nigra, locomotor behavior deficits, and age-dependent formation of abnormal α-synuclein protein aggregates. Here we briefly review new developments in genetic rat models of PD that may have greater potential for identifying underlying mechanisms, for discovering novel therapeutic targets, and for developing greatly needed treatments to slow or halt disease progression. © 2018 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease; Protein Kinases; Rats; Rats, Transgenic; Ubiquitin-Protein Ligases

The link between protein aggregation and neurodegenerative disease is well established. However, given the heterogeneity of species formed during the aggregation process, it is difficult to delineate details of the molecular events involved in generating pathological aggregates from those producing soluble monomers. As aberrant aggregates are possible pharmacological targets for the treatment of neurodegenerative diseases, the need to observe and characterise soluble oligomers has pushed traditional biophysical techniques to their limits, leading to the development of a plethora of new tools capable of detecting soluble oligomers with high precision and specificity. In this review, we discuss a range of modern biophysical techniques that have been developed to study protein aggregation, and give an overview of how they have been used to understand, in detail, the aberrant aggregation of amyloidogenic proteins associated with the two most common neurodegenerative disorders, Alzheimer's disease and Parkinson's disease.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Parkinson Disease; Protein Aggregates; tau Proteins

It has been known for decades that degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs in both Alzheimer's disease (AD) and Parkinson's disease (PD), but it was given scant attention. It is now recognized that hyperphosphorylated tau in the LC is the first detectable AD-like neuropathology in the human brain, α-synuclein inclusions in the LC represent an early step in PD, and experimental LC lesions exacerbate neuropathology and cognitive/behavioral deficits in animal models. The purpose of this review is to consider the causes and consequences of LC pathology, dysfunction, and degeneration, as well as their implications for early detection and treatment.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Cognitive Dysfunction; Humans; Locus Coeruleus; Neurons; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disorder with complex etiology and variable pathology. While a subset of cases is associated with single-gene mutations, the majority originates from a combination of factors we do not fully understand. Thus, understanding the underlying causes of PD is indispensable for the development of novel therapeutics. Glycation, the non-enzymatic reaction between reactive dicarbonyls and amino groups, gives rise to a variety of different reaction products known as advanced glycation end products (AGEs). AGEs accumulate over a proteins life-time, and increased levels of glycation reaction products play a role in diabetic complications. It is now also becoming evident that PD patients also display perturbed sugar metabolism and protein glycation, including that of alpha-synuclein, a key player in PD. Here, we hypothesize that anti-diabetic drugs targeting the levels of glycation precursors, or promoting the clearance of glycated proteins may also prove beneficial for PD patients.

Topics: alpha-Synuclein; Diabetes Complications; Glucose; Glycation End Products, Advanced; Glycosylation; Homeostasis; Humans; Hypoglycemic Agents; Maillard Reaction; Parkinson Disease; Protein Processing, Post-Translational; Pyruvaldehyde; Risk Factors

Parkinson's disease is characterized by the loss of nigrostriatal dopaminergic signaling and the presence of alpha-synuclein aggregates (also called Lewy bodies and neurites) throughout the brain. In 2003, Braak and colleagues created a staging system for Parkinson's disease describing the connection between the alpha-synuclein pathology and disease severity. Later, they suggested that the pathology might initially be triggered by exogenous insults targeting the gut and olfactory system. In 2008, we and other groups documented Lewy pathology in grafted neurons in people with Parkinson's disease who had been transplanted over a decade prior to autopsy. We proposed that the Lewy pathology in the grafted neurons was the result of permissive templating or prion-like spread of alpha-synuclein pathology from neurons in the host to those in the grafts. During the following ten years, several studies described the transmission of alpha-synuclein pathology between neurons, both in cell culture and in experimental animals. Recent research has also begun to identify underlying molecular mechanisms. Collectively, these experimental studies tentatively support the idea that the progression from one Braak stage to the next is the consequence of prion-like propagation of Lewy pathology. However, definitive proof that intercellular propagation of alpha-synuclein pathology occurs in Parkinson's disease cases has proven difficult to secure. In this review, we highlight several open questions that currently prevent us from concluding with certainty that prion-like transfer of alpha-synuclein contributes to the progression of Parkinson's disease.

Topics: alpha-Synuclein; Animals; Connectome; Humans; Neurons; Parkinson Disease; Prions; Protein Aggregates

Current understanding of the pathophysiology of Parkinson's disease suggests a key role of the accumulation of alpha-synuclein in the pathogenesis. This critical review highlights major landmarks, hypotheses and controversies about the origin and progression of synucleinopathy in Parkinson's disease, leading to an updated review of evidence suggesting the enteric nervous system might be the starting point for the whole process. Although accumulating and compelling evidence favors this theory, the remaining knowledge gaps are important points for future studies.

Topics: alpha-Synuclein; Brain; Disease Progression; Enteric Nervous System; Humans; Parkinson Disease

Parkinson's disease is a progressive neurodegenerative disease characterized by Lewy body pathology of which the primary constituent is aggregated misfolded alpha-synuclein protein. Currently, there are no clinical therapies for treatment of the underlying alpha-synuclein dysfunction and accumulation, and the standard of care for patients with Parkinson's disease focuses only on symptom management, creating an immense therapeutic gap that needs to be filled. Defects in autophagy have been strongly implicated in Parkinson's disease. Here, we review evidence from human, mouse, and cell culture studies to briefly explain these defects in autophagy in Parkinson's disease and the necessity for autophagy to be carefully and precisely tuned to maintain neuron survival. We summarize recent experimental agents for treating alpha-synuclein accumulation in α-synuclein Parkinson's disease and related synucleinopathies. Most of the efforts for developing experimental agents have focused on immunotherapeutic strategies, but we discuss why those efforts are misplaced. Finally, we emphasize why increasing autophagy flux for alpha-synuclein clearance is the most promising therapeutic strategy. Activating autophagy has been successful in preclinical models of Parkinson's disease and yields promising results in clinical trials.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Autophagy; Drug Development; Drug Evaluation, Preclinical; Humans; Mice; Parkinson Disease

The discovery of genetic links between alpha-synuclein and PD has opened unprecedented opportunities for research into a new group of diseases, now collectively known as synucleinopathies. Autonomic dysfunction, including cardiac sympathetic denervation, has been reported in familial forms of synucleinopathies that have Lewy bodies at the core of their pathogenesis. SNCA mutations and multiplications, LRRK2 disease with Lewy bodies as well as other common, sporadic forms of idiopathic PD, MSA, pure autonomic failure, and dementia with Lewy bodies have all been associated with dysautonomia. By contrast, in familial cases of parkinsonism without Lewy bodies, such as in PARK2, the autonomic profile remains normal throughout the course of the disease. The degeneration of the central and peripheral autonomic systems in genetic as well as sporadic forms of neurodegenerative synucleinopathies correlates with the accumulation of alpha-synuclein immunoreactive-containing inclusions. Given that dysautonomia has a significant impact on the quality of life of sufferers and autonomic symptoms are generally treatable, a prompt diagnostic testing and treatment should be provided. Moreover, new evidence suggests that autonomic dysfunction can be used as an outcome prediction factor in some forms of synucleinopathies or premotor diagnostic markers that could be used in the future to define further research avenues. In this review, we describe the autonomic dysfunction of genetic synucleinopathies in comparison to the dysautonomia of sporadic forms of alpha-synuclein accumulation and provide the reader with an up-to-date overview of the current understanding in this fast-growing field. © 2018 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Autonomic Nervous System Diseases; Humans; Mutation; Parkinson Disease

The second-most common neurodegenerative disease, Parkinson's Disease (PD) has three hallmarks: dysfunctional dopamine transmission due, at least in part, to dopamine neuron degeneration; intracellular inclusions of α-synuclein aggregates; and neuroinflammation. The origin and interplay of these features remains a puzzle, as does the underlying mechanism of PD pathogenesis and progression. When viewed in the context of neuroimmunology, dopamine also plays a role in regulating peripheral immune cells. Intriguingly, plasma dopamine levels are altered in PD, suggesting collateral dysregulation of peripheral dopamine transmission. The dopamine transporter (DAT), the main regulator of dopaminergic tone in the CNS, is known to exist in lymphocytes and monocytes/macrophages, but little is known about peripheral DAT biology or how DAT regulates the dopaminergic tone, much less how peripheral DAT alters immune function. Our review is guided by the hypothesis that dysfunctional peripheral dopamine signaling might be linked to the dysfunctional immune responses in PD and thereby suggests a potential bidirectional communication between central and peripheral dopamine systems. This review seeks to foster new perspectives concerning PD pathogenesis and progression.

Topics: alpha-Synuclein; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Humans; Lymphocytes; Macrophages; Monocytes; Nerve Degeneration; Neurodegenerative Diseases; Parkinson Disease; Signal Transduction

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by elevated concentrations of glucose in the blood. The chronic hyperglycemic state accounts for most of the vascular complications associated to the disease and the prevalent mechanism proposed is related to the glycating chemistry mediated by methylglyoxal (MG), which accumulates in T2DM. In recent years, a higher risk of Parkinson's disease (PD) onset in people affected by T2DM has become evident, but the molecular mechanisms underlying the interplay between T2DM and PD are still unknown. The oxidative chemistry of dopamine and its reactivity towards the protein α-Synuclein (aS) has been associated to the pathogenesis of PD. Recently, aS has also been described to interact with MG. Interestingly, MG and the dopamine oxidation products share both structural similarity and chemical reactivity. The ability of MG to spread over the site of its production and react with aS could represent the rationale to explain the higher incidence of PD in T2DM-affected people and may open opportunities for the development of novel strategies to antagonize the raise of PD.

Topics: alpha-Synuclein; Animals; Diabetes Mellitus, Type 2; Dopamine; Humans; Models, Biological; Parkinson Disease; Risk Factors

Parkinson's disease (PD) is the second most common neurodegenerative disorder. It is characterized by the accumulation of intracellular α-synuclein aggregates and the degeneration of nigrostriatal dopaminergic neurons. While no treatment strategy has been proven to slow or halt the progression of the disease, there is mounting evidence from preclinical PD models that activation of 5'-AMP-activated protein kinase (AMPK) may have broad neuroprotective effects. Numerous dietary supplements and pharmaceuticals (e.g., metformin) that increase AMPK activity are available for use in humans, but clinical studies of their effects in PD patients are limited. AMPK is an evolutionarily conserved serine/threonine kinase that is activated by falling energy levels and functions to restore cellular energy balance. However, in response to certain cellular stressors, AMPK activation may exacerbate neuronal atrophy and cell death. This review describes the regulation and functions of AMPK, evaluates the controversies in the field, and assesses the potential of targeting AMPK signaling as a neuroprotective treatment for PD.

Topics: alpha-Synuclein; AMP-Activated Protein Kinases; Animals; Autophagy; Brain; Dopaminergic Neurons; Humans; Neuroprotective Agents; Parkinson Disease; Signal Transduction

Several age-related neurodegenerative disorders are characterized by the deposition of aberrantly folded endogenous proteins. These proteins have prion-like propagation and amplification properties but so far appear nontransmissible between individuals. Because of the features they share with the prion protein, PrP, the characteristics of pathogenic protein aggregates in several progressive brain disorders, including different types of Lewy body diseases (LBDs), such as Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), have been actively investigated. Even though the pleomorphic nature of these syndromes might suggest different underlying causes, ɑ-synuclein (ɑSyn) appears to play an important role in this heterogeneous group of diseases (the synucleinopathies). An attractive hypothesis is that different types of ɑSyn protein assemblies have a unique and causative role in distinct synucleinopathies. We will discuss the recent research progress on ɑSyn assemblies involved in PD, MSA and DLB; their behavior as strains; current spreading hypotheses; their ability to seed centrally and peripherally; and their implication for disease pathogenesis.

Topics: alpha-Synuclein; Animals; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Prions; Protein Aggregates

The greatest unmet medical need in Parkinson's disease (PD) is treatments that slow the relentless progression of symptoms. The discovery of genetic variants causing and/or increasing the risk for PD has provided the field with a new arsenal of potential therapies ready to be tested in clinical trials. We highlight 3 of the genetic discoveries (α-synuclein, glucocerebrosidase, and leucine-rich repeat kinase) that have prompted new therapeutic approaches now entering the clinical stages. We are at an exciting juncture in the journey to developing disease-modifying treatments based on knowledge of PD genetics and pathology. This review focuses on therapeutic paradigms that are under clinical development and highlights a wide range of key outstanding questions in PD. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Animals; Clinical Trials as Topic; Glucosylceramidase; Humans; Parkinson Disease; Protein Serine-Threonine Kinases

Parkinson's disease is the most common neurodegenerative movement disorder. It arises as a result of neuronal cell death in specific brain regions, notably the substantia nigra pars compacta, and is characterized by the accumulation of α-synuclein in these brain regions. Current pharmacological therapies alleviate the motor symptoms of the disease and are particularly effective in the early stages of the disease. Ongoing drug development efforts focus on disease-modifying strategies that aim to halt or slow disease progression. In this review, we explore a number of emerging disease-modifying strategies with a focus on direct and indirect targeting of α-synuclein dysfunction. We summarize newer classes of small molecules and biological agents intended to attenuate protein aggregation or to target enzymes that may increase the degradation of the pathogenic forms of α-synuclein. Finally, we discuss emerging strategies that are demonstrating the potential for disease modification at the preclinical stage.

Topics: Acetylglucosamine; Adrenergic beta-Agonists; alpha-Synuclein; Animals; Gastrointestinal Microbiome; Humans; Parkinson Disease

Neurodegenerative disorders, such as Alzheimer's, Parkinson's, and prion diseases, are directly linked to the formation and accumulation of protein aggregates in the brain. These aggregates, principally made of proteins or peptides that clamp together after acquisition of β-folded structures, also contain heparan sulfates. Several lines of evidence suggest that heparan sulfates centrally participate in the protein aggregation process. In vitro, they trigger misfolding, oligomerization, and fibrillation of amyloidogenic proteins, such as Aβ, tau, α-synuclein, prion protein, etc. They participate in the stabilization of protein aggregates, protect them from proteolysis, and act as cell-surface receptors for the cellular uptake of proteopathic seeds during their spreading. This review focuses attention on the importance of heparan sulfates in protein aggregation in brain disorders including Alzheimer's, Parkinson's, and prion diseases. The presence of these sulfated polysaccharides in protein inclusions in vivo and their capacity to trigger protein aggregation in vitro strongly suggest that they might play critical roles in the neurodegenerative process. Further advances in glyco-neurobiology will improve our understanding of the molecular and cellular mechanisms leading to protein aggregation and neurodegeneration.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Heparitin Sulfate; Humans; Models, Chemical; Parkinson Disease; Prion Diseases; Prion Proteins; Protein Aggregates

This review addresses the role of α-synuclein (αSyn) in the etiopathology of Parkinson's disease (PD), with emphasis on its interaction with GM1 ganglioside. We begin with a brief review of some of the milestone discoveries that helped to elucidate PD neuropathology, including the fibrous inclusions of Lewy that characterize the degenerating dopaminergic neurons of the substantia nigra and the presence of αSyn as a major constituent of these Lewy bodies and neurites. This enabled Braak et al. to define the progressive nature of PD in developing their staging hypothesis which described the topographically predictable sequence of neuropathological changes giving rise to prodromal nonmotor symptoms that precede the classical motor dysfunctions. We recount recent studies demonstrating strong, specific binding of αSyn to GM1 that serves to inhibit fibril formation and the key role of N-acetylation of αSyn in enhancing GM1 binding and specificity. The consequences of insufficient GM1 are illustrated in a newly presented mouse model of PD based on partial deletion of this ganglioside due to heterologous disruption of B4galnt1 (GM2/GD2 synthase), such mice presenting accurate recapitulation of the PD phenotype. A key feature of these mice was marked elevation of αSyn aggregates which accompanied motor impairment, both aggregates and motor dysfunction being corrected by GM1 replacement therapy. Such therapy was achieved with high dosage of GM1 and more effectively with lower doses of LIGA20, a membrane permeable analog of GM1. The accuracy of this mouse model was emphasized by the finding that various central nervous system and noncentral nervous system tissues from PD patients manifested similar GM1 deficiency as the B4galnt1

Topics: alpha-Synuclein; Animals; Gangliosides; Humans; Parkinson Disease

Parkinson's disease (PD) is one of the most common diseases associated with neurodegenerative disorders. It affects 3% to 4% of the population over the age of 65 years. The neuropathological dominant symptoms of PD include the destruction of neurons in the substantia nigra, thus causing striatal dopamine deficiency and the presence of intracellular inclusions that contain aggregates of α‑synuclein. The premature form of PD is familial and is known as early onset PD (EOPD). It involves a small portion of patients with PD, displaying symptoms before the age of 60 years. Although individuals who are suffering from the EOPD may have genetic changes, the molecular mechanisms that differentiate between EOPD and late onset PD (LOPD) remain unclear. Owing to the complexity of discriminating between the different forms, treatment, and management of PD, the identification of biomarkers for early diagnosis seems necessary. For this purpose, many studies have been undertaken for the introduction of several biological molecules through various techniques as potential biomarkers. The main focus of these studies was on α-synuclein. However, there are other molecules that are potential biomarkers, such as microRNAs and peptoids. In this article, we tried to review some of these studies.

Topics: alpha-Synuclein; Biomarkers; Humans; MicroRNAs; Parkinson Disease; Peptoids

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Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Camellia sinensis; Catechin; Cerebral Cortex; Humans; Molecular Docking Simulation; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Tea

Neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) impose a pressing burden on our developed and consequently aging society. Misfolded protein aggregates are a critical aspect of several neurodegenerative diseases. Nevertheless, several questions remain unanswered regarding the role of misfolded protein aggregates and the cause of neuronal cell death. Recently, it has been postulated that neuroinflammatory processes might play a crucial role in the pathogenesis of PD. Numerous postmortem, brain imaging, epidemiological, and animal studies have documented the involvement of the innate and adaptive immunity in neurodegeneration. Whether these inflammatory processes are directly involved in the etiology of PD or represent secondary consequences of nigrostriatal pathway injury is the subject of intensive research. Immune alterations in response to extracellular

Topics: alpha-Synuclein; Animals; Apoptosis; Humans; Inflammation; Neurodegenerative Diseases; Neurogenic Inflammation; Neurons; Parkinson Disease; Proteostasis Deficiencies

REP1 is a polymorphic dinucleotide repeat sequence located in the promoter region of the SNCA gene (OMIM 163890). Opinions regarding the interaction between the various REP1 alleles and Parkinson's disease (PD) or its phenotypes have been inconsistent and have thus far not been comprehensively analyzed. In this study, we searched Medline, Embase and Cochrane databases as well as the Chinese-language Wanfang and CNKI databases using strict inclusion and exclusion criteria and conducted our analysis using Revman 5.3 software. Our search produced 28 articles describing REP1 alleles and their associated PD risks and 8 articles which discussed the relationship between REP1 variation and PD phenotypes. We found that the 265-, 269-, and 271-bp alleles of REP1 (using the nomenclature established by Xia et al.) increased the risk of PD (OR: 1.81, 1.05, 1.17; p: 0.0002, 0.003, 0.002) while the 267-bp allele decreased PD risk (OR: 0.86, p: <0.00001) when taking all populations into account. By ethnicity, we observed an obvious population heterogeneity in the effects of various alleles, where the 269-, 271-, and 273-bp alleles increased PD risk (OR: 1.06, 1.22, 1.89; p: 0.001, 0.003, 0.001) and the 267-bp allele decreased PD risk (OR: 0.85; p: <0.00001) in Caucasian populations, and the 263- and 265-bp alleles increased the risk of PD (OR: 2.22, 2.03; p: 0.03, 0.0002) and the 267- and 273-bp alleles decreased PD risk (OR: 0.90, 0.78; p: 0.02, 0.03) in Asian populations. We also determined that the 267-, 269-, and 271-bp alleles occurred the most frequently, although the frequency distribution varied among different ethnicities. Phenotypic analysis demonstrated that PD patients carrying the 271-bp allele were prone to early onset PD (OR: 1.75, p: 0.02) while the 267-bp had the opposite effect (OR: 0.81; p: 0.01).

Topics: Adaptor Proteins, Signal Transducing; alpha-Synuclein; Asian People; Genetic Predisposition to Disease; Humans; Parkinson Disease; White People

Rapid eye movement (REM) sleep behavior disorder (RBD) involves REM sleep without atonia in conjunction with a recurrent nocturnal dream enactment behavior, with vocalizations such as shouting and screaming, and motor behaviors such as punching and kicking. Secondary RBD is well described in association with neurological disorders including Parkinson's disease (PD), multiple system atrophy (MSA), and other conditions involving brainstem structures such as tumors. However, RBD alone is now considered to be a potential harbinger of later development of neurodegenerative disorders, in particular PD, MSA, dementia with Lewy bodies (DLB), and pure autonomic failure. These conditions are linked by their underpinning pathology of alpha-synuclein protein aggregation. In RBD, it is therefore important to recognize the potential risk for later development of an alpha-synucleinopathy, and to investigate for other potential causes such as medications. Other signs and symptoms have been described in RBD, such as orthostatic hypotension, or depression. While it is important to recognize these features to improve patient management, they may ultimately provide clinical clues that will lead to risk stratification for phenoconversion. A critical need is to improve our ability to counsel patients, particularly with regard to prognosis. The ability to identify who, of those with RBD, is at high risk for later neurodegenerative disorders will be paramount, and would in addition advance our understanding of the prodromal stages of the alpha-synucleinopathies. Moreover, recognition of at-risk individuals for neurodegenerative disorders may ultimately provide a platform for the testing of possible neuroprotective agents for these neurodegenerative disorders.

Topics: alpha-Synuclein; Cross-Sectional Studies; Electroencephalography; Humans; Lewy Body Disease; Longitudinal Studies; Multiple System Atrophy; Parkinson Disease; REM Sleep Behavior Disorder

Over 100 years ago, Lewy bodies and Lewy neurites were defined as a pathologic hallmark of Parkinson disease. Eighty years later, α-synuclein was found to be the primary component of these inclusions. Emerging evidence suggests that α-synuclein pathology propagates across interconnected networks throughout the nervous system in a prion-like manner. Pathologic α-synuclein seeds aggregation of native α-synuclein, resulting in the formation of insoluble inclusions. These seeds can propagate within the neuron and to interconnected neurons, resulting in the spread of pathology throughout the brain. Here, we discuss how the findings that α-synuclein pathology spreads throughout the nervous system has revolutionized our understanding about Parkinson disease pathogenesis and resulted in the development of novel therapeutic strategies to halt disease progression.

Topics: alpha-Synuclein; Animals; Brain; Disease Progression; Humans; Parkinson Disease; Prions; Protein Aggregation, Pathological; Proteostasis Deficiencies

Misfolding and aggregation of the proteins amyloid-β, tau and alpha-synuclein is the predominant pathology underlying the neurodegenerative disorders, Alzheimer's and Parkinson's disease. While end stage insoluble products of aggregation have been well characterised in human and animal models of disease, accumulating evidence from biophysical, cellular and in vivo studies has shown that soluble intermediates of aggregation, or oligomers, may be the key species that mediate toxicity and underlie seeding and spreading in disease. Here, we review the process of protein misfolding, and the intrinsic and extrinsic processes that cause the native states of the key aggregating proteins to undergo conformational change to form oligomers and ultimately fibrils. We discuss the structural features of the key toxic intermediate, and describe the putative mechanisms by which oligomers may cause cell toxicity. Finally, we explore the potential therapeutic approaches raised by the oligomer hypothesis in neurodegenerative disease.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Parkinson Disease; Protein Aggregates; Protein Conformation; tau Proteins

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra and the intraneuronal Lewy bodies in this area. Genetic mutations in PD pathogenesis have been explored and better understood in recent years. GBA variants are now considered to be the single largest risk factor for PD. Gaucher disease (GD) is a lysosomal storage disorder disease and an inherited deficiency of lysosomal glucocerebrosidase (GCase) arising from mutations in the gene GBA. A group of patients with GD exhibit parkinsonian symptoms, meanwhile, GBA mutations are more frequently observed in patients with PD. These lines of evidence suggest a close relationship between GBA mutations and PD. GBA mutations are associated with an earlier onset age and a distinct cognitive decline in PD. GCase loss-of-function caused by GBA mutations interferes with the degradation of α-synuclein, and α-synuclein pathology in turn inhibits normal GCase function in PD, which forms a vicious cycle. However, the exact mechanisms for this bidirectional pathogenic loop have not to be fully elucidated. In this review, we summarize the current understandings on the potential link between GBA mutations and PD pathogenesis, which may show novel insights into PD etiology and therapeutics.

Topics: alpha-Synuclein; Cognitive Dysfunction; Dopaminergic Neurons; Gaucher Disease; Glucosylceramidase; Humans; Mutation; Parkinson Disease; Parkinsonian Disorders; Risk Factors; Substantia Nigra

Parkinson's disease is a common neurodegenerative disorder presenting with a variety of motor and non-motor symptoms. The motor symptoms manifest as a result of the progressive degeneration of midbrain dopaminergic neurons. The axons of these neurons project to the striatum as the nigrostriatal pathway, which is a crucial part of the basal ganglia circuitry controlling movement. In addition to the neuronal degeneration, abnormal intraneuronal α-synuclein protein inclusions called Lewy bodies and Lewy neurites increase in number and spread throughout the nervous system as the disease progresses. While the loss of midbrain dopaminergic neurons is well-established as being central to motor symptoms, there is an increasing focus on the timing of nigrostriatal degeneration, with preclinical evidence suggesting that early axonal degeneration may play a key role in the early stages of Parkinson's disease. Here we review recent evidence for early midbrain dopaminergic axonal degeneration in patients with Parkinson's disease, and explore the potential role of α-synuclein accumulation in this process, with a focus on studies in human populations at the imaging, post-mortem, cellular and molecular levels. Finally, we discuss the implications of this for neurotrophic factor therapies for Parkinson's disease.

Topics: alpha-Synuclein; Animals; Axons; Dopaminergic Neurons; Early Diagnosis; Humans; Nerve Degeneration; Parkinson Disease

Apart from the characteristic and progressive motor- and movement-related problems, Parkinson's disease (PD) patients also suffer from several non-motor symptoms, including gastrointestinal dysfunction. The fact that the enteric nervous system (ENS) controls motility and that one of the typical PD hallmarks, α-synuclein-positive deposits, has also been found in the intestinal wall have rendered the ENS and the gut a popular subject of study in the context of PD. The possibility that these deposits could serve as an early biomarker is obviously of tremendous medical benefit but also the idea that the gut may possibly be a gateway via which the disease is initiated and progressively makes its way via the peripheral nerves to the central nervous system has increased the interest in the ENS-PD link. Furthermore, the fact that gastrointestinal symptoms are present in PD suggests that the ENS might be affected as well. However, despite a large body of literature on the topic, the actual role or the magnitude of involvement of the ENS in PD remains elusive. The multitudes of experimental approaches and animal models have complicated the interpretation of results and the outcome of different studies does not necessarily align well. In this review, we chose to highlight some elements of interest and some items of confusion, particularly those where research should be focusing. We also list a number of open questions in the field that could serve as a guideline for future, preferably concerted research.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Enteric Nervous System; Gastrointestinal Diseases; Humans; Parkinson Disease; Protein Aggregates

α-Synuclein (α-syn) is a 140-amino acid protein, the physiological function of which has yet to be clarified. It is involved in several neurodegenerative disorders, and the interaction of the protein with brain lipids plays an important role in the pathogenesis of Parkinson's disease (PD). Polyunsaturated fatty acids (PUFA) are highly abundant in the brain where they play critical roles in neuronal membrane fluidity and permeability, serve as energy reserves and function as second messengers in cell signaling. PUFA concentration and composition in the brain are altered with age when also an increase of lipid peroxidation is observed. Considering that PD is clearly correlated with oxidative stress, PUFA abundance and composition became of great interest in neurodegeneration studies because of PUFA's high propensity to oxidize. The high levels of the PUFA docosahexaenoic acid (DHA) in brain areas containing α-syn inclusions in patients with PD further support the hypothesis of possible interactions between α-syn and DHA. Additionally, a possible functional role of α-syn in sequestering the early peroxidation products of fatty acids was recently proposed. Here, we provide an overview of the current knowledge regarding the molecular interactions between α-syn and fatty acids and the effect exerted by the protein on their oxidative state. We highlight recent findings supporting a neuroprotective role of the protein, linking α-syn, altered lipid composition in neurodegenerative disorders and PD development.

Topics: alpha-Synuclein; Animals; Fatty Acids, Unsaturated; Humans; Neurodegenerative Diseases; Parkinson Disease

Neurodegenerative disorders have been and remain persistent sources of enormous suffering throughout human history. The tragedy of their impact on human relationships, physical vitality, and fundamental dignity cannot be understated. Parkinson's disease (PD), one of the most common of these terrible illnesses, has a global incidence of approximately two-to-four percent of the human population, along with devastating social and economic impact. The present review analyzes aspects of PD pathophysiology that offer particularly attractive strategies for the development of improved prevention and therapy. The occurrence, symptoms, pathogenesis, and etiology of PD are considered, with focus on how the Alpha synuclein protein, which normally regulates neurotransmitter release, is aggregated by oxidative stressors into toxic inclusions, prominently including Lewy bodies and insoluble fibrils that disrupt the organization of brain areas responsible for motor control. The contribution to a progressively prooxidant tissue environment resulting from interaction between advanced glycation end products (AGEs) and their cognate receptors (RAGEs) is examined here as a significant driver of PD. This review also explores strategies currently being developed by a U.S.-Russian team that may reduce the risk and severity of PD by use of recombinant atoxic derivatives (ad) of botulinum neurotoxins (BoNT/A ad), that traffic inducers of the cytoprotective enzyme heme oxygenase to selected midbrain neurons, at which Alpha synuclein aggregation occurs. Considered together, the topic material presented here provides both researchers and clinicians with a short but concise overview of the current understanding of PD pathology and approaches to biotherapeutic (precision) countermeasures to its onset and progression.

Topics: Adaptation, Physiological; alpha-Synuclein; Antiparkinson Agents; Gene Expression Regulation, Enzymologic; Heme Oxygenase (Decyclizing); Humans; Parkinson Disease

Protein aggregation is a hallmark of many neurodegenerative diseases. In Parkinson's disease protein misfolding of α-synuclein involves conformational changes in the protein structure that often results in self-association and aggregation leading to accumulation of α-synuclein in neuronal cells. The underlying mechanisms by which aggregations can lead to impaired cellular functions are often not understood. Meanwhile, there is growing evidence that links mitochondrial dysfunction to Parkinson's disease. As both mitochondria and protein aggregation of α-synuclein have been shown to play a major role in Parkinson's disease, it seems likely that a converging mechanism exists that links the two pathways.

Topics: alpha-Synuclein; Animals; Humans; Mitochondria; Neurodegenerative Diseases; Parkinson Disease; Protein Conformation

Parkinson's disease (PD), the second most common neurodegenerative disease after Alzheimer's disease, develops sporadically, and its cause is unknown. However, 5-10% of PD cases are inherited as monogenic diseases, which provides a chance to understand the molecular mechanisms underlying neurodegeneration. Over 20 causative genes have already been identified and are being characterized. These PD-associated genes are broadly classified into two groups: genes involved in mitochondrial functions and genes related to membrane dynamics such as intracellular vesicle transport and the lysosomal pathway. In this review, we summarize the latest findings on the mechanism by which members of the latter group of PD-associated genes regulate membrane dynamics, and we discuss how mutations of these genes lead to dopaminergic neurodegeneration.

Topics: alpha-Synuclein; Animals; Autophagy; Cell Membrane; Endocytosis; Humans; Parkinson Disease; Synaptic Vesicles

The cardinal motor symptoms of Parkinson's disease (PD) are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). Alpha-synuclein (aSYN) pathology and mitochondrial dysfunction have been implicated in PD pathogenesis, but until recently it was unclear why SNc dopaminergic neurons should be particularly vulnerable to these two types of insult. In this brief review, the evidence that SNc dopaminergic neurons have an anatomical, physiological, and biochemical phenotype that predisposes them to mitochondrial dysfunction and synuclein pathology is summarized. The recognition that certain traits may predispose neurons to PD-linked pathology creates translational opportunities for slowing or stopping disease progression.

Topics: alpha-Synuclein; Animals; Calcium; Dopaminergic Neurons; Humans; Mitochondria; Oxidative Stress; Parkinson Disease

Large-scale genome-wide association study (GWAS) has identified that the alpha-synuclein (SNCA) rs11931074 polymorphism is associated with Parkinson's disease (PD) susceptibility in individuals of Japanese descent. Subsequently, a number of replication studies have been performed in Asian and Caucasian populations. However, the results remain controversial due to the relatively small sample sizes and genetic heterogeneity. Here, to overcome the limitations of individual studies, we reevaluated this association with data from 33 independent studies involving 15,368 patients and 29,710 control samples identified by searching PubMed and EMBase databases. Odds ratios (OR) with 95% confidence interval (CI) were applied to assess the association between SNCA rs11931074 polymorphism and PD. Heterogeneity, sensitivity analysis, and publication bias were conducted to measure the robustness of our findings. Using allele, recessive, dominant, and additive models, we did not reveal significant heterogeneity among 33 studies. Significant association of the SNCA rs11931074 polymorphism with PD was observed (T vs. G: OR = 1.36, 95% CI = 1.31-1.42; TT vs. TG + GG: OR = 1.58, 95% CI = 1.46-1.72; TT + TG vs. GG: OR = 1.44, 95% CI = 1.35-1.55; TT vs. GG: OR = 1.87, 95% CI = 1.68-2.09) in the pooled populations. Furthermore, subgroup analyses accounting for ethnicity found similar significant results in both Asian and Caucasian populations. In conclusion, our meta-analysis further indicates that the SNCA rs11931074 polymorphism contributes to PD susceptibility. We believe that our findings will be very useful for future genetic studies on PD.

Topics: Alleles; alpha-Synuclein; Asian People; Female; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Odds Ratio; Parkinson Disease; Polymorphism, Single Nucleotide; Risk Factors; White People

Parkinson's disease (PD) is a neurodegenerative disorder whose aetiology remains unclear: degeneration involves several neurotransmission systems, resulting in a heterogeneous disease characterized by motor and non-motor symptoms. PD causes progressive disability that responds only to symptomatic therapies. Future advances include neuroprotective strategies for use in at-risk populations before the clinical onset of disease, hence the continuing need to identify reliable biomarkers that can facilitate the clinical diagnosis of PD. In this evaluative review, we summarize information on potential diagnostic biomarkers for use in the clinical and preclinical stages of PD.

Topics: alpha-Synuclein; Biomarkers; Brain; Cognition Disorders; Constipation; Depression; Early Diagnosis; Genetic Predisposition to Disease; Humans; Inflammation; Levodopa; Metabolomics; Microbiota; Movement Disorders; Neuroimaging; Olfaction Disorders; Parkinson Disease; REM Sleep Behavior Disorder; Symptom Assessment; Vision Disorders

Parkinson's disease (PD) is the second most common neurodegenerative disorder. It is characterized by the degeneration of nigral dopaminergic (DA) neurons. While over 90% of cases are idiopathic, without a clear etiology, mutations in many genes have been linked to rare, familial forms of PD. It has been quite challenging to develop effective animal models of PD that capture salient features of PD. The discovery of induced pluripotent stem cells (iPSCs) makes it possible to generate patient-specific DA neurons to study PD. Here, we review the methods for the generation of iPSCs and discuss previous studies using iPSC-derived neurons from monogenic forms of PD. These investigations have revealed several converging pathways that intersect with the unique vulnerabilities of human nigral DA neurons. With the rapid development in stem cell biology, it is possible to generate patient-specific neurons that will be increasingly similar to those in the brain of the patient. Combined with the ability to edit the genome to generate isogenic iPSCs, the generation and analysis of patient-specific midbrain DA neurons will transform PD research by providing a valuable tool for mechanistic study and drug discovery.

Topics: alpha-Synuclein; Dopaminergic Neurons; Humans; Induced Pluripotent Stem Cells; Models, Biological; Parkinson Disease; Substantia Nigra; Ubiquitin-Protein Ligases

Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia that is characterized by loss of muscle atonia during REM sleep (known as REM sleep without atonia, or RSWA) and abnormal behaviours occurring during REM sleep, often as dream enactments that can cause injury. RBD is categorized as either idiopathic RBD or symptomatic (also known as secondary) RBD; the latter is associated with antidepressant use or with neurological diseases, especially α-synucleinopathies (such as Parkinson disease, dementia with Lewy bodies and multiple system atrophy) but also narcolepsy type 1. A clinical history of dream enactment or complex motor behaviours together with the presence of muscle activity during REM sleep confirmed by video polysomnography are mandatory for a definite RBD diagnosis. Management involves clonazepam and/or melatonin and counselling and aims to suppress unpleasant dreams and behaviours and improve bedpartner quality of life. RSWA and RBD are now recognized as manifestations of an α-synucleinopathy; most older adults with idiopathic RBD will eventually develop an overt neurodegenerative syndrome. In the future, studies will likely evaluate neuroprotective therapies in patients with idiopathic RBD to prevent or delay α-synucleinopathy-related motor and cognitive decline.

Topics: alpha-Synuclein; Antidepressive Agents; Central Nervous System Depressants; Clonazepam; Diagnosis, Differential; Humans; Mass Screening; Melatonin; Parkinson Disease; Polysomnography; Prevalence; REM Sleep Behavior Disorder; Risk Factors; Sex Factors

Protein intracellular inclusions within the central nervous system are hallmarks of several progressive neurodegenerative disorders in man. The protein constituents of those deposits and the affected regions within the brain differ from one neurodegenerative disorder to another. Until recently, the vicious circle consisting of spread, seeded assembly and accumulation over time within the central nervous system of misfolded proteins aggregates was thought to be restricted to the prion protein PrP. Recent reports suggest that other protein aggregates spread and amplify within the central nervous system leading to distinct diseases. How alpha-synuclein protein assemblies traffic between cells, amplify by recruiting endogenous monomeric alpha-synuclein and cause distinct synucleinopathies is unclear. I review here the experimental evidence supporting the propagation of alpha-synuclein mega-dalton assemblies in a manner similar to prion protein aggregates. I also describe how alpha-synuclein aggregates. I also explain why the aggregation of alpha-synuclein may lead to distinct synucleinopathies.

Topics: alpha-Synuclein; Humans; Parkinson Disease; Prion Diseases

In Parkinson's disease, the progressive neurodegeneration of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta (SNc) is associated with classic motor features, which typically have a focal onset. Since a defined somatotopic arrangement in the SNc has not been recognized, this focal motor onset is unexplained and hardly justified by current pathogenic theories of bottom-up disease progression (Braak's hypothesis, prionopathy). Here we propose that corticostriatal activity may represent a critical somatotopic "stressor" for nigrostriatal terminals, ultimately driving retrograde nigrostriatal degeneration and leading to focal motor onset and progression of Parkinson's disease. As a pathogenic mechanism, corticostriatal activity may promote secretion of striatal extracellular alpha-synuclein, favoring its pathological aggregation at vulnerable dopaminergic synapses. A similar pathogenic process may occur at corticofugal projections to the medulla oblongata and other vulnerable structures, thereby contributing to the bottom-up progression of Lewy pathology. This cortical pathogenesis may co-exist with bottom-up mechanisms, adding an integrative top-down perspective to the quest for the factors that impinge upon the vulnerability of dopaminergic cells in the onset and progression of Parkinson's disease.

Topics: alpha-Synuclein; Animals; Brain Mapping; Corpus Striatum; Dopaminergic Neurons; Humans; Parkinson Disease; Substantia Nigra

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting older individuals. The specific cause underlying dopaminergic (DA) neuron loss in the substantia nigra, a pathological hallmark of PD, remains elusive. Here, we highlight peer-reviewed reports using induced pluripotent stem cells (iPSCs) to model PD in vitro and discuss the potential disease-relevant phenotypes that may lead to a better understanding of PD etiology. Benefits of iPSCs are that they retain the genetic background of the donor individual and can be differentiated into specialized neurons to facilitate disease modeling.. Mitochondrial dysfunction, oxidative stress, ER stress, and alpha-synuclein accumulation are common phenotypes observed in PD iPSC-derived neurons. New culturing technologies, such as directed reprogramming and midbrain organoids, offer innovative ways of investigating intraneuronal mechanisms of PD pathology. PD patient-derived iPSCs are an evolving resource to understand PD pathology and identify therapeutic targets.

Topics: alpha-Synuclein; Cell Differentiation; Dopamine; Dopaminergic Neurons; Humans; Induced Pluripotent Stem Cells; Oxidative Stress; Parkinson Disease; Phenotype

The role of autoimmunity in Parkinson's disease (PD), as one of the most popular research subjects, has been intensively investigated in recent years. Although the ultimate cause of PD is unknown, one major area of interest remains identifying new therapeutic targets and options for patients suffering from PD. Herein, we present a comprehensive review of the impacts of autoimmunity in neurodegenerative diseases, especially PD, and we have composed a logical argument to substantiate that autoimmunity is actively involved in the pathogenesis of PD through several proteins, including α-synuclein, DJ-1, PINK1, and Parkin, as well as immune cells, such as dendritic cells, microglia, T cells, and B cells. Furthermore, a detailed analysis of the relevance of autoimmunity to the clinical symptoms of PD provides strong evidence for the close correlation of autoimmunity with PD. In addition, the previously identified relationships between other autoimmune diseases and PD help us to better understand the disease pattern, laying the foundation for new therapeutic solutions to PD. In summary, this review aims to integrate and present currently available data to clarify the pathogenesis of PD and discuss some controversial but innovative research perspectives on the involvement of autoimmunity in PD, as well as possible novel diagnostic methods and treatments based on autoimmunity targets.

Topics: alpha-Synuclein; Animals; Autoantigens; Autoimmunity; B-Lymphocytes; Brain; Dendritic Cells; Disease Models, Animal; Humans; Microglia; Mutation; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; T-Lymphocytes; Ubiquitin-Protein Ligases

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia following Alzheimer disease. It stems from the formation of Lewy bodies, which contain aggregates of the misfolded protein, α-synuclein. These deposit in areas of the nervous system and brain, leading to neuronal cell death and causing clinically apparent symptoms. Because of its clinical overlap with other forms of dementia, DLB is often underdiagnosed and misdiagnosed. There is currently no cure for DLB and treatments are aimed at ameliorating specific symptoms.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Behavioral Symptoms; Biomarkers; Diagnosis, Differential; Disease Management; Humans; Lewy Body Disease; Parkinson Disease

This comprehensive MDSGene review is devoted to the three autosomal-dominant PD forms: PARK-SNCA, PARK-LRRK2, and PARK-VPS35. It follows MDSGene's standardized data extraction protocol, screened a total of 2,972 citations, and is based on fully curated phenotypic and genotypic data on 937 patients with dominantly inherited PD attributed to 44 different mutations in SNCA, LRRK2, or VPS35. All of these data are also available in an easily searchable online database (www.mdsgene.org), which additionally provides descriptive summary statistics on phenotypic and genetic data. Despite the high degree of missingness of phenotypic features and unsystematic reporting of genotype data in the original literature, the present review recapitulates many of the previously described findings including later onset of disease (median age at onset: ∼49 years) compared to recessive forms of PD of an overall excellent treatment response. Our systematic review validates previous reports showing that SNCA mutation carriers have a younger age at onset compared to LRRK2 and VPS35 (P < 0.001). SNCA mutation carriers often have additional psychiatric symptoms, and although not exclusive to only LRRK2 or VPS35 mutation carriers, LRRK2 mutation carriers have a typical form of PD, and, lastly, VPS35 mutation carriers have good response to l-dopa. © 2018 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Genotype; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Parkinson Disease; Phenotype; Vesicular Transport Proteins

Parkinson's disease (PD) is characterized by the presence of insoluble protein clusters containing α-synuclein. Impairment of mitochondria, endoplasmic reticulum, autophagy and intracellular trafficking proper function has been suggested to be caused by α-synuclein toxicity, which is also associated with the higher levels of ROS found in the aged brain and in PD. Oxidative stress leads to protein oligomerization and aggregation that impair autophagy and mitochondrial dynamics leading to a vicious cycle of organelles damage and neurodegeneration. In this review we focused on the role of α-synuclein dysfunction as a cellular stressor that impairs mitochondria, endoplasmic reticulum, autophagy and cellular dynamics culminating with dopaminergic depletion and the pathogenesis of PD.

Topics: alpha-Synuclein; Amino Acid Sequence; Animals; Autophagy; Endoplasmic Reticulum; Humans; Mitochondria; Oxidative Stress; Parkinson Disease; Protein Transport; Reactive Oxygen Species

The greatest unmet therapeutic need in Parkinson's disease (PD) is a treatment that slows the relentless progression of the symptoms and the neurodegenerative process. This review highlights the utility of genetics to understand the pathogenic mechanisms and develop novel therapeutic approaches for PD. The focus is on strategies provided by genetic studies: notably via the reduction and clearance of α-synuclein, inhibition of LRRK2 kinase activity, and modulation of glucocerebrosidase-related substrates. In addition, the critical role of precompetitive public-private partnerships in supporting trial design optimization, overall drug development, and regulatory approvals is illustrated. With these great advances, the promise of developing transformative therapies that halt or slow disease progression is a tangible goal.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Clinical Trials as Topic; Drug Delivery Systems; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disorder resulting from degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). PD is characterized by motor dysfunctions as well as gastrointestinal symptoms and mental impairment. The pathological hallmark of PD is an accumulation of misfolded α-synuclein aggregates within the brain. The etiology of PD and related synucleinopathy is poorly understood, but recently, the hypothesis that α-synuclein pathology spreads in a prion-like fashion originating in the gut has gained much scientific attention. A crucial clue was the appearance of constipation before the onset of motor symptoms, gut dysbiosis and synucleinopathy in PD patients. Another line of evidence, demonstrating accumulation of α-synuclein within the peripheral autonomic nervous system (PANS), including the enteric nervous system (ENS), and the dorsal motor nucleus of the vagus (DMV) support the concept that α-synuclein can spread from the ENS to the brain by the vagus nerve. The decreased risk of PD following truncal vagotomy supports this. The convincing evidence of the prion-like behavior of α-synuclein came from postmortem observations that pathological α-synuclein inclusions appeared in healthy grafted neurons. In this review, we summarize the available data from human subjects' research and animal experiments, which seem to be the most suggestive for explaining the hypotheses.

Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Gastrointestinal Diseases; Humans; Parkinson Disease; Prion Diseases

Parkinson disease has been considered for practical purposes a heterogeneous clinico-pathological entity. The operational definition requires clinical ascertainment of a levodopa-responsive parkinsonism with no "atypical" features, and pathological criteria based on the finding, usually at postmortem, of aggregates of α-synuclein in Lewy bodies and Lewy neurites. The underlying assumption has been that a molecular-biological disorder, targetable for disease modification as a whole, underlies this clinico-pathologic, convergent model of disease. The 2020s will be expected to mark the beginning of the end for this model, especially if therapeutic success in a specific molecular subtype, such as PD-GBA, is not translated to "sporadic PD". The complex and dynamic biological abnormalities of aging, which have informed the evolution of other fields in medicine into divergent, systems-biology models, will also provide the template for the development of disease modifying therapies for neurodegenerative disorders. In the 2020s and 2030s we will no longer ask whether any given molecule may be neuroprotective in early Parkinson disease but, rather, which subtype (which endophenotype) among the Parkinson diseases would be the best mechanistic recipient for such molecule and which would not. The next breakthrough in Parkinson's research will be conceptual: the recognition that discoveries in a subtype of PD will apply only or largely to that subtype and not construed to represent "a piece" that seamlessly inserts into, and helps explains, a unifying "Parkinson's puzzle". Successful neuroprotection for each PD subtype will likely require pharmacotherapeutic combinations ("drug cocktails") to harness synergistic potential benefits when more than the dominant pathogenic mechanism is targeted, as identified from forthcoming population-based unbiased biomarker discovery programs.

Topics: alpha-Synuclein; Brain; Disease Management; Humans; Lewy Bodies; Parkinson Disease; Parkinsonian Disorders; Systems Biology

In the last two decades it has become clear that Parkinson's disease (PD) is associated with a plethora of gastrointestinal symptoms originating from functional and structural changes in the gut and its associated neural structures. This is of particular interest not only because such symptoms have a major impact on the quality of life of PD patients, but also since accumulating evidence suggests that in at least a subgroup of patients, these disturbances precede the motor symptoms and diagnosis of PD by years and may thus give important insights into the origin and pathogenesis of the disease. In this mini-review we attempt to concisely summarize the current knowledge after two decades of research on the gut-brain axis in PD. We focus on alpha-synuclein pathology, biomarkers, and the gut microbiota and envision the development and impact of these research areas for the two decades to come.

Topics: alpha-Synuclein; Biomarkers; Brain; Enteric Nervous System; Gastrointestinal Microbiome; Humans; Parkinson Disease

Clinical definitions of Parkinson's disease (PD) are over 200 years old, while neuropathological definitions- which are still the basis of how we define the disease now- are over 100 years old. We argue that for both clinical care and therapeutic development, these definitions need updating for the molecular age in which we live. We highlight specific instances in which genetic or biochemical biomarkers are increasingly used for clinical trial enrollment in the neurodegenerative diseases, suggesting that molecular definition(s) of PD are already emerging. We review candidate biomarkers for PD-related pathologies and highlight the need for further validation.

Topics: alpha-Synuclein; Biomarkers; Brain; Disease Progression; Humans; Parkinson Disease

Given the rapidly increasing number of reported movement disorder genes and clinical-genetic desciptions of mutation carriers, the International Parkinson's Disease and Movement Disorder Society Gene Database (MDSGene) initiative has been launched in 2016 and grown to become a large international project (http://www.mdsgene.org). MDSGene currently contains >1150 variants described in ∼5700 movement disorder patients in almost 1000 publications including monogenic forms of PD clinically resembling idiopathic (PARK-PINK1, PARK-Parkin, PARK-DJ-1, PARK-SNCA, PARK-VPS35, PARK-LRRK2), as well as of atypical PD (PARK-SYNJ1, PARK-DNAJC6, PARK-ATP13A2, PARK-FBXO7). Inclusion of genes is based on standardized published criteria for determining causation. Clinical and genetic information can be filtered according to demographic, clinical or genetic criteria and summary statistics are automatically generated by the MDSGene online tool. Despite MDSGene's novel approach and features, it also faces several challenges: i) The criteria for designating genes as causative will require further refinement, as well as time and support to replace the faulty list of 'PARKs'. ii) MDSGene has uncovered extensive clinical data gaps. iii) The quickly growing body of clinical and genetic data require a large number of experts worldwide posing logistic challenges. iv) MDSGene currently captures published data only, i.e., a small fraction of the available information on monogenic PD available. Thus, an important future aim is to extend MDSGene to unpublished cases in order to provide the broad data base to the PD community that is necessary to comprehensively inform genetic counseling, therapeutic approaches and clinical trials, as well as basic and clinical research studies in monogenic PD.

Topics: alpha-Synuclein; Databases, Genetic; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease; Protein Kinases; Ubiquitin-Protein Ligases

α-Synuclein is an abundant neuronal protein that is highly enriched in presynaptic nerve terminals. Genetics and neuropathology studies link α-synuclein to Parkinson's disease (PD) and other neurodegenerative disorders. Accumulation of misfolded oligomers and larger aggregates of α-synuclein defines multiple neurodegenerative diseases called synucleinopathies, but the mechanisms by which α-synuclein acts in neurodegeneration are unknown. Moreover, the normal cellular function of α-synuclein remains debated. In this perspective, we review the structural characteristics of α-synuclein, its developmental expression pattern, its cellular and subcellular localization, and its function in neurons. We also discuss recent progress on secretion of α-synuclein, which may contribute to its interneuronal spread in a prion-like fashion, and describe the neurotoxic effects of α-synuclein that are thought to be responsible for its role in neurodegeneration.

Topics: alpha-Synuclein; Animals; Humans; Mice; Mice, Transgenic; Neurons; Parkinson Disease; Synapses

The field of gene therapy has recently witnessed a number of major conceptual changes. Besides the traditional thinking that comprises the use of viral vectors for the delivery of a given therapeutic gene, a number of original approaches have been recently envisaged, focused on using vectors carrying genes to further modify basal ganglia circuits of interest. It is expected that these approaches will ultimately induce a therapeutic potential being sustained by gene-induced changes in brain circuits. Among others, at present, it is technically feasible to use viral vectors to (1) achieve a controlled release of neurotrophic factors, (2) conduct either a transient or permanent silencing of any given basal ganglia circuit of interest, (3) perform an in vivo cellular reprogramming by promoting the conversion of resident cells into dopaminergic-like neurons, and (4) improving levodopa efficacy over time by targeting aromatic L-amino acid decarboxylase. Furthermore, extensive research efforts based on viral vectors are currently ongoing in an attempt to better replicate the dopaminergic neurodegeneration phenomena inherent to the progressive intraneuronal aggregation of alpha-synuclein. Finally, a number of incoming strategies will soon emerge over the horizon, these being sustained by the underlying goal of promoting alpha-synuclein clearance, such as, for instance, gene therapy initiatives based on increasing the activity of glucocerebrosidase. To provide adequate proof-of-concept on safety and efficacy and to push forward true translational initiatives based on these different types of gene therapies before entering into clinical trials, the use of non-human primate models undoubtedly plays an instrumental role.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Genetic Therapy; Genetic Vectors; Parkinson Disease; Primates

Topics: alpha-Synuclein; Gene Expression; Genome-Wide Association Study; Humans; Lewy Body Disease; Multiple System Atrophy; Mutation; Parkinson Disease; Phenotype

Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed of aggregates of alpha-synuclein protein. Accumulating evidence, including genome-wide association studies, has implicated the alpha-synuclein (SNCA) gene in the etiology of synucleinopathies and it has been suggested that SNCA expression levels are critical for the development of these diseases. This review focuses on genetic variants from the class of structural variants (SVs), including multiplication of large genomic segments and short (<50bp) genomic variants such as simple sequence repeats (SSRs), within the SNCA locus. We provide evidence that SNCA-SVs play a key role in the pathogenesis of synucleinopathies via their effects on gene expression and on regulatory mechanisms including transcription and splicing.

Topics: alpha-Synuclein; Genomic Structural Variation; Humans; Microsatellite Repeats; Neurodegenerative Diseases; Parkinson Disease; Protein Aggregation, Pathological; Protein Conformation

Parkinson disease is the second-most common neurodegenerative disorder that affects 2-3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α-synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability. The underlying molecular pathogenesis involves multiple pathways and mechanisms: α-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport and neuroinflammation. Recent research into diagnostic biomarkers has taken advantage of neuroimaging in which several modalities, including PET, single-photon emission CT (SPECT) and novel MRI techniques, have been shown to aid early and differential diagnosis. Treatment of Parkinson disease is anchored on pharmacological substitution of striatal dopamine, in addition to non-dopaminergic approaches to address both motor and non-motor symptoms and deep brain stimulation for those developing intractable L-DOPA-related motor complications. Experimental therapies have tried to restore striatal dopamine by gene-based and cell-based approaches, and most recently, aggregation and cellular transport of α-synuclein have become therapeutic targets. One of the greatest current challenges is to identify markers for prodromal disease stages, which would allow novel disease-modifying therapies to be started earlier.

Topics: alpha-Synuclein; Antiparkinson Agents; Biomarkers; Dopamine Agonists; Genetic Therapy; Humans; Levodopa; Mitochondria; Oxidative Stress; Parkinson Disease; Quality of Life

Parkinson's disease (PD) is a progressively debilitating neurodegenerative syndrome. It is best described as a movement disorder characterized by motor dysfunctions, progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta, and abnormal intraneuronal protein aggregates, named Lewy bodies and Lewy neurites. Nevertheless, knowledge of the molecular events leading to this pathophysiology is incomplete. To date, only mutations in the α-synuclein and LRRK2-encoding genes have been associated with typical findings of clinical and pathologic PD. LRRK2 appears to have a central role in the pathogenesis of PD as it is associated with α-synuclein pathology and other proteins implicated in neurodegeneration. Thus, LRRK2 dysfunction may influence the accumulation of α-synuclein and its pathology through diverse pathomechanisms altering cellular functions and signaling pathways, including immune system, autophagy, vesicle trafficking, and retromer complex modulation. Consequently, development of novel LRRK2 inhibitors can be justified to treat the neurodegeneration associated with abnormal α-synuclein accumulation.

Topics: alpha-Synuclein; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Nerve Degeneration; Parkinson Disease

Biochemical alterations found in the brains of Parkinson's disease (PD) patients indicate that cellular stress is a major driver of dopaminergic neuronal loss. Oxidative stress, mitochondrial dysfunction, and ER stress lead to impairment of the homeostatic regulation of protein quality control pathways with a consequent increase in protein misfolding and aggregation and failure of the protein degradation machinery. Ubiquitin signalling plays a central role in protein quality control; however, prior to genetic advances, the detailed mechanisms of how impairment in the ubiquitin system was linked to PD remained mysterious. The discovery of mutations in the α-synuclein gene, which encodes the main protein misfolded in PD aggregates, together with mutations in genes encoding ubiquitin regulatory molecules, including PTEN-induced kinase 1 (PINK1), Parkin, and FBX07, has provided an opportunity to dissect out the molecular basis of ubiquitin signalling disruption in PD, and this knowledge will be critical for developing novel therapeutic strategies in PD that target the ubiquitin system.

Topics: alpha-Synuclein; Animals; Humans; Oxidative Stress; Parkinson Disease; Ubiquitin; Ubiquitin-Protein Ligases

Understanding regulation of α-synuclein has long been a central focus for Parkinson's disease (PD) researchers. Accumulation of this protein in the Lewy body or neurites, mutations in the coding region of the gene and strong association of α-synuclein encoding gene multiplication (duplication/triplication) with familial form of PD have indicated the importance of this molecule in pathogenesis of the disease. Several years of research identified many potential faulty pathways associated with accumulation of α-synuclein inside dopaminergic neurons and its transmission to neighboring ones. Concurrently, an appreciable body of research is growing to understand the epigenetic and genetic deregulation of α-synuclein that might contribute to the disease pathology. Completion of the ENCODE (Encyclopedia of DNA Elements) project and recent advancement made in the epigenetic and trans factor mediated regulation of each gene, has tremendously accelerated the need to carefully understand the epigenetic structure of the gene (SNCA) encoding α-synuclein protein in order to decipher the regulation and contribution of α-synuclein to the pathogenesis of PD. We have also analyzed the detailed epigenetic structure of this gene with knowledge from ENCODE database, which may open new avenues in α-synuclein research. Interestingly, we have found that the gene contains several transcriptionally activate histone modifications and associated potential transcription factor binding sites in the non-coding areas that strongly suggest alternative regulatory pathways. Altogether this review will provide interesting insight of α-synuclein gene regulation from epigenetic, genetic and post-transcriptional perspectives and their potential implication in the PD pathogenesis.

Topics: alpha-Synuclein; Animals; Epigenesis, Genetic; Gene Expression Regulation; Humans; Parkinson Disease

Neurodegenerative diseases are highly debilitating conditions characterised primarily by progressive neuronal loss and impairment of the nervous system. Parkinson's disease (PD) is one of the most common of these disorders, affecting 1-2% of the population above the age of 65. Although the underlying mechanisms of PD have been extensively studied, we still lack a full understanding of the molecular underpinnings of the disease. Thus, the in vitro and in vivo models currently used are able to only partially recapitulate the typical phenotypes of the disease. Here, we review various cell culture models currently used to study the molecular basis of PD, with a focus on alpha-synuclein-associated molecular pathologies. We also discuss how different cell models may constitute powerful tools for high-throughput screening of molecules capable of modulating alpha-synuclein toxicity.

Topics: alpha-Synuclein; Animals; Cell Line; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Parkinson Disease; Phenotype

Parkinson's disease (PD) is the second most common neurodegenerative disorder that is characterized by progressive movement disability and a variety of non-motor symptoms. The neuropathology of PD consists of the loss of dopaminergic neurons in the midbrain and the appearance of neuronal inclusions called Lewy bodies, which contain insoluble α-synuclein, a relatively small protein originally identified in association with synaptic vesicles in the presynaptic nerve terminals. Drugs that replenish dopamine can partly alleviate the motor symptoms, but they do not cure the disease itself. Therefore, there is an urgent need for disease modification in terms of the delay or prevention of neurodegeneration. Recent advances in genetic and biochemical studies have provided unifying conceptual frameworks of the pathogenesis of PD. Particularly, membrane trafficking has aroused special attention as an initiator or enhancer of the neurodegenerative process that leads to PD. Defects in the cellular trafficking pathway result in synaptic dysfunction and the accumulation of misfolded α-synuclein. Likewise, changes in intracellular sorting and degradation profoundly influence the cellular trafficking of misfolded proteins, thereby facilitating the cell-to-cell spreading of hazardous α-synuclein species in a prion-like manner. Here, we will review our current knowledge of the functional roles of membrane trafficking in PD and will discuss how this cellular process could induce or facilitate the functional and pathological alterations in this disease.

Topics: alpha-Synuclein; Cell Death; Cell Membrane; Humans; Models, Biological; Neurons; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease, whose prevalence is projected to be between 8.7 and 9.3 million by 2030. Until about 20 years ago, PD was considered to be the textbook example of a "non-genetic" disorder. Nowadays, PD is generally considered a multifactorial disorder that arises from the combination and complex interaction of genes and environmental factors. To date, a total of 7 genes including SNCA, LRRK2, PARK2, DJ-1, PINK 1, VPS35 and ATP13A2 have been seen to cause unequivocally Mendelian PD. Also, variants with incomplete penetrance in the genes LRRK2 and GBA are considered to be strong risk factors for PD worldwide. Although genetic studies have provided valuable insights into the pathogenic mechanisms underlying PD, the role of structural variation in PD has been understudied in comparison with other genomic variations. Structural genomic variations might substantially account for such genetic substrates yet to be discovered. The present review aims to provide an overview of the structural genomic variants implicated in the pathogenesis of PD.

Topics: alpha-Synuclein; Biomarkers; Exons; Genetic Predisposition to Disease; Genomics; Genotype; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease; Phenotype; Prevalence; Protein Deglycase DJ-1; Protein Kinases; Proton-Translocating ATPases; Risk Factors; Spain; Ubiquitin-Protein Ligases; Vesicular Transport Proteins

Parkinson's disease (PD) is a common neurodegenerative condition affecting more than 8 million people worldwide. Although, the majority of PD cases are sporadic in nature, there are a growing number of monogenic mutations identified to cause PD in a highly penetrant manner. Many of these familial mutations give rise to a condition that is clinically and neuropathologically similar, if not identical, to sporadic PD. Mutations in genes such as SNCA cause PD in an autosomal dominant manner and patients have motor and non-motor symptoms that are typical for sporadic PD. With the advent of reprogramming technology it is now possible to capture these mutations in induced pluripotent stem cells (iPSCs) to establish models of PD in a dish. There are multiple neuronal subtypes affected in PD including the midbrain dopaminergic (mDA) neurons of the substantia nigra. Robust neuronal differentiation into mDA or other relevant neural cell types are critical to accurately model the disease and ensure the findings are relevant to understanding the disease process. Another challenge for establishing accurate models of PD is being met by the generation of isogenic control iPSC lines with precise correction of mutations using advanced gene editing technology. The contributions of ageing and environmental factors present further challenges to this field, but significant progress is being made in these areas to establish highly relevant and robust models of PD. These human neuronal models, used in conjunction with other model systems, will vastly improve our understanding of the early stages of the PD, which will be key to identifying disease-modifying and preventative treatments.

Topics: alpha-Synuclein; Animals; Humans; Induced Pluripotent Stem Cells; Models, Biological; Mutation; Parkinson Disease

Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease.

Topics: alpha-Synuclein; Animals; Dopamine; Dopaminergic Neurons; Humans; Iron; Parkinson Disease; Protein Processing, Post-Translational

Parkinson's disease (PD) is a complex and phenotypically heterogeneous neurodegenerative disease, for which the diagnosis is mainly based on clinical parameters (even if neuroimaging plays a role in diagnostic assessment); as a consequence, misdiagnosis is common, especially in early stages. Thus, there is an urgent need of having available biomarkers in order to achieve an early and accurate diagnosis. Since molecular changes in the brain are reliably and timely reflected in cerebrospinal fluid (CSF), CSF represents an ideal source for biomarkers of different pathophysiological processes characterizing the disease since its early phases. Areas covered: The aim of this review is to provide an update on the role, development and validation of most studied CSF biomarkers showing a role in the diagnosis and/or prognosis of PD. Oligomeric alpha-synuclein, DJ-1, lysosomal enzymes (namely, glucocerebrosidase) show consistent evidence as potential diagnostic biomarkers of PD. Neurofilament light chain may also have a significant role in differentiating PD from other parkinsonisms. Amyloid beta peptide 1-42 has consistently shown a prognostic value in terms of development of cognitive impairment and dementia in PD patients. Expert commentary: CSF biomarkers represent a very promising approach to early and differential diagnosis of PD. The biomarkers available so far need preanalytical and analytical validation in order to have these CSF biomarkers ready for clinical use.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Biomarkers; Glucosylceramidase; Humans; Neurofilament Proteins; Parkinson Disease; Peptide Fragments; Protein Deglycase DJ-1

Parkinson's disease (PD) is a progressive neurodegenerative disorder implicitly marked by the substantia nigra dopaminergic neuron degeneration and explicitly characterized by the motor and non-motor symptom complexes. Apart from the nigrostriatal dopamine depletion, the immune and endocrine study findings are also frequently reported, which, in fact, have helped to broaden the symptom spectrum and better explain the pathogenesis and progression of PD. Nevertheless, based on the neural, immune, and endocrine findings presented above, it is still difficult to fully recapitulate the pathophysiologic process of PD. Therefore, here, in this review, we have proposed the neuroimmunoendocrine (NIE) modulatory network in PD, aiming to achieve a more comprehensive interpretation of the pathogenesis and progression of this disease. As a matter of fact, in addition to the classical motor symptoms, NIE modulatory network can also underlie the non-motor symptoms such as gastrointestinal, neuropsychiatric, circadian rhythm, and sleep disorders in PD. Moreover, the dopamine (DA)-melatonin imbalance in the retino-diencephalic/mesencephalic-pineal axis also provides an alternative explanation for the motor complications in the process of DA replacement therapy. In conclusion, the NIE network can be expected to deepen our understanding and facilitate the multi-dimensional management and therapy of PD in future clinical practice.

Topics: alpha-Synuclein; Animals; Circadian Clocks; Dopamine; Dopaminergic Neurons; Genetic Predisposition to Disease; Humans; Hypothalamus; Inflammation; Melatonin; Nerve Degeneration; Parkinson Disease; Receptors, Cytoplasmic and Nuclear; Receptors, Dopamine; Weight Loss

Parkinson's disease (PD) is a multifactorial progressive neurological disorder. Pathological hallmarks of PD are characterized by the presence of α-synuclein (αSyn) aggregates known as Lewy bodies. αSyn aggregation is one of the leading causes for the neuronal dysfunction and death in PD. It is also associated with neurotransmitter and calcium release. Current therapies of PD are limited to only symptomatic relief without addressing the underlying pathogenic factors of the disease process such as aggregation of αSyn. Consequently, the progression of the disease continues with the current therapies. Therefore, the modulation of αSyn aggregation is an emerging approach as a novel therapeutic target to treat PD. There are two major aspects that might be targeted therapeutically: first, protein is prone to aggregation, therefore, anti-aggregative or compounds that can break the pre-existing aggregates should be helpful. Second, there are number of molecular events that may be targeted to combat the disease.

Topics: alpha-Synuclein; Humans; Parkinson Disease; Protein Aggregates; Small Molecule Libraries

α-synuclein is a small protein abundantly expressed in the brain and mainly located in synaptic terminals. The conversion of α-synuclein into oligomers and fibrils is the hallmark of a range of neurodegenerative disorders including Parkinson's disease and dementia with Lewy bodies. α-synuclein is disordered in solution but can adopt an α-helical conformation upon binding to lipid membranes. This lipid-protein interaction plays an important role in its proposed biological function, i.e., synaptic plasticity, but can also entail the aggregation of the protein. Both the chemical properties of the lipids and the lipid-to-protein-ratio have been reported to modulate the aggregation propensity of α-synuclein. In this review, the influence of changes in the nature and levels of lipids on the aggregation propensity of α-synuclein in vivo and in vitro will be discussed within a common general framework. In particular, while biophysical measurements and kinetic analyses of the time courses of α-synuclein aggregation in the presence of different types of lipid vesicles allow a mechanistic dissection of the influence of the lipids on α-synuclein aggregation, biological studies of cellular and animal models of Parkinson's disease allow the determination of changes in lipid levels and properties associated with the disease.

Topics: alpha-Synuclein; Animals; Humans; Membrane Lipids; Parkinson Disease; Protein Aggregation, Pathological

PD is a common and a debilitating degenerative movement disorder. The number of patients is increasing worldwide and as yet there is no cure for the disease. The majority of existing treatments target motor symptom control. Over the last two decades the impact of the genetic contribution to PD has been appreciated. Significant discoveries have been made, which have advanced our understanding of the pathophysiological and molecular basis of PD. In this chapter we outline current knowledge of the clinical aspects of PD and the basic mechanistic understanding.

Topics: alpha-Synuclein; Autonomic Nervous System Diseases; Brain; Dementia; Glucosylceramidase; Humans; Hypokinesia; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Bodies; Mitochondria; Muscle Rigidity; Olfaction Disorders; Oxidative Stress; Parkinson Disease; Postural Balance; Protein Aggregation, Pathological; Protein Deglycase DJ-1; Sleep Wake Disorders; Tremor; Ubiquitin-Protein Ligases

Several neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, are characterized by prominent loss of synapses and neurons associated with the presence of abnormally structured or misfolded protein assemblies. Cell-to-cell transfer of misfolded proteins has been proposed for the intra-cerebral propagation of these diseases. When released, misfolded proteins diffuse in the 3D extracellular space before binding to the plasma membrane of neighboring cells, where they diffuse on a 2D plane. This reduction in diffusion dimension and the cell surface molecular crowding promote deleterious interactions with native membrane proteins, favoring clustering and further aggregation of misfolded protein assemblies. These processes open up new avenues for therapeutics development targeting the initial interactions of deleterious proteins with the plasma membrane or the subsequent pathological signaling.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyotrophic Lateral Sclerosis; Animals; Cell Membrane; Extracellular Space; Humans; Huntingtin Protein; Huntington Disease; Neurodegenerative Diseases; Parkinson Disease; Prions; Protein Aggregation, Pathological; Protein Folding; Protein Transport; Superoxide Dismutase-1; tau Proteins

Parkinson's disease (PD) is a progressive brain disorder that interferes with activities of normal life. The main pathological feature of this disease is the loss of more than 80% of dopamine-producing neurons in the substantia nigra (SN). Dopaminergic neuronal cell death occurs when intraneuronal, insoluble, aggregated proteins start to form Lewy bodies (LBs), the most important component of which is a protein called α-synuclein (α-syn). α-Syn structurally contains hexameric repeats of 11 amino acids, which are characteristic of apolipoproteins and thus α-syn can also be considered an apolipoprotein. Moreover, apolipoproteins seem to be involved in the incidence and development of PD. Some apolipoproteins such as ApoD have a neuroprotective role in the brain. In PD, apoD levels increase in glial cells surrounding dopaminergic cells. However, elevated levels of some other apolipoproteins such as ApaA1 and ApoE are reported as a vulnerability factor of PD. At present, when a clinical diagnosis of PD is made, based on symptoms such as shaking, stiff muscles and slow movement, serious damage has already been done to nerve cells of the SN. The diagnosis of PD in its earlier stages, before this irreversible damage, would be of enormous benefit for future treatment strategies designed to slow or halt the progression of PD. This review presents the roles of apolipoproteins and α-syn in PD and how some of them could potentially be used as biomarkers for PD.

Topics: alpha-Synuclein; Animals; Apolipoproteins; Cholesterol; Humans; Parkinson Disease

Cerebrospinal fluid (CSF) is sequestered from blood by the blood-brain barrier and directly communicates with brain parenchymal interstitial fluid, leading to contain specific biomarkers of neurological diseases.. CSF contains glycan isoforms of transferrin (Tf): one appears to be derived from the brain and the other from blood.. CSF contains two glycan-isoforms; brain-type Tf and serum-type Tf. Glycan analysis and immunohistochemistry suggest that serum-type Tf having α2, 6sialylated glycans is derived from blood whereas brain-type Tf having GlcNAc-terminated glycans is derived from the choroid plexus, CSF producing tissue. The ratio of serum-type/brain-type Tf differentiates Alzheimer's disease from idiopathic normal pressure hydrocephalus, which is an elderly dementia caused by abnormal metabolism of CSF. The ratios in Parkinson's disease (PD) patients were higher than those of controls and did not appear to be normally distributed. Indeed, detrended normal Quantile-Quantile plot analysis reveals the presence of an independent subgroup showing higher ratios in PD patients. The subgroup of PD shows higher levels of CSF α-synuclein than the rest, indicating that PD includes two subgroups, which differ in levels of brain-type Tf and α-synuclein.. Glycosylation in central nervous system appears to be unique. The unique glycan may be a tag for glycoprotein, which is biosynthesized in the central nervous system. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa.

Topics: alpha-Synuclein; Biomarkers; Choroid Plexus; Dementia; Diagnosis, Differential; Glycosylation; Humans; Hydrocephalus, Normal Pressure; Parkinson Disease; Polysaccharides; Protein Isoforms; Protein Processing, Post-Translational; Transferrin

Parkinson's disease biomarkers are needed to increase diagnostic accuracy, to objectively monitor disease progression and to assess therapeutic efficacy as well as target engagement when evaluating novel drug and therapeutic strategies. This article summarizes perianalytical considerations for biomarker studies (based on immunoassays) in Parkinson's disease, with emphasis on quantifying total α-synuclein protein in biological fluids. Current knowledge and pitfalls are discussed, and selected perianalytical variables are presented systematically, including different temperature of sample collection and types of collection tubes, gradient sampling, the addition of detergent, aliquot volume, the freezing time, and the different thawing methods. We also discuss analytical confounders. We identify gaps in the knowledge and delineate specific areas that require further investigation, such as the need to identify posttranslational modifications of α-synuclein and antibody-independent reference methods for quantification, as well as the analysis of potential confounders, such as comorbidities, medication, and phenotypes of Parkinson's disease in larger cohorts. This review could be used as a guideline for future Parkinson's disease biomarker studies and will require regular updating as more information arises in this growing field, including new technical developments as they become available. In addition to reviewing best practices, we also identify the current technical limitations and gaps in the knowledge that should be addressed to enable accurate and quantitative assessment of α-synuclein levels in the clinical setting. © 2017 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Biomarkers; Humans; Parkinson Disease

This article reviews current treatment strategies and recent advances for the Lewy body dementias (LBDs). Current available symptom treatment strategies are based on monoaminergic, cholinergic and glutaminergic neurotransmitter systems. Relatively robust evidence exists for cholinesterase inhibitors for cognitive impairment in LBD and in Parkinson's disease for antidepressants, clozapine and recently pimavanserin for psychosis. interpidine (RVT 101) and nelotanserin are currently under investigation. Non-pharmacological interventions, such as cognitive stimulation, physical exercises and neuromodulation strategies, may be useful in Parkinson's disease but have not yet been tested in dementias. Disease-modifying approaches are aimed at preventing, slowing or ameliorating the production, aggregation and deposition of pathological proteins, including immunotherapy targeting α-synuclein and an ongoing trial using ambroxol which increases glucocerebrosidase activity to lower the levels of the protein alpha-synuclein. Other disease-modifying clinical trials are using agents to augment insulin signalling, stem cell therapy, reducing amyloid pathology and gene therapy.

Topics: alpha-Synuclein; Cholinesterase Inhibitors; Disease Management; Genetic Therapy; Humans; Lewy Body Disease; Parkinson Disease; Piperidines; Stem Cell Transplantation; Urea

A major challenge in Parkinson disease (PD) will be to turn an emerging and expanding pipeline of novel disease-modifying candidate compounds into therapeutics. Novel targets need in vivo validation, and candidate therapeutics require appropriate preclinical platforms on which to define potential efficacy and target engagement before advancement to clinical development. We propose that α-synuclein (α-syn)-based mammalian models will be crucial for this process. Here, we review α-syn transgenic mouse models, viral vector models of α-syn overexpression and models of 'prion-like' spread of α-syn, and describe how each of these model types may contribute to PD drug discovery. We conclude by presenting our opinion on how to use a combination of these models through the late-stage preclinical, proof-of-principle investigation of novel therapeutics.

Topics: alpha-Synuclein; Animals; Animals, Genetically Modified; Antiparkinson Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Parkinson Disease

With the understanding that α-synuclein plays a major role in the pathogenesis of Parkinson's disease (PD), novel animal models have been developed for conducting preclinical research in screening novel disease modifying therapies. Advancements in research techniques in α-synuclein targeted disease modification have utilised methods such as viral mediated expression of human α-synuclein, as well as the inoculation of pathogenic α-synuclein species from Lewy Bodies of PD patients, for accurately modelling progressive self-propagating neurodegeneration. In applying these cutting-edge research tools with sophisticated trial designs in preclinical drug trials, a useful platform has emerged for developing candidate agents with disease modifying actions, promising a greater chance of success for clinical translation. In this article, we describe the transition of well-established animal models of PD symptomatology to newly developed models of PD pathogenesis, with specific focus on methods of viral-mediated and inoculation of pathogenic α-synuclein, that aim to aid scientific translation of neuroprotective strategies.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Humans; Lewy Bodies; Mutagenesis, Site-Directed; Neurons; Parkinson Disease

From kinetic data (k, T) we calculated the thermodynamic parameters for various processes (nucleation, elongation, fibrillization, etc.) of proteinaceous diseases that are related to the β-amyloid protein (Alzheimer's), to tau protein (Alzheimer's, Pick's), to α-synuclein (Parkinson's), prion, amylin (type II diabetes), and to α-crystallin (cataract). Our calculations led to ΔG

Topics: alpha-Crystallins; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Cataract; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Islet Amyloid Polypeptide; Oxidative Stress; Oxygen; Parkinson Disease; Singlet Oxygen; tau Proteins; Thermodynamics

Alpha-synuclein is a protein implicated in Parkinson's disease and thought to be one of the main pathological drivers in the disease, although it remains unclear how this protein elicits its neurotoxic effects. Recent findings indicate that the assembly of toxic oligomeric species of alpha-synuclein may be one of the key processes for the pathology and spread of the disease. The absence of a sensitive in situ detection method has hindered the study of these oligomeric species and the role they play in the human brain until recently. In this review, we assess the evidence for the toxicity and prion-like activity of oligomeric forms of alpha-synuclein and discuss the advances in our understanding of the role of alpha-synuclein in Parkinson's disease that may be brought about by the specific and sensitive detection of distinct oligomeric species in post-mortem patient brain. Finally, we discuss current approaches being taken to therapeutically target alpha-synuclein oligomers and their implications.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Biomarkers; Humans; Parkinson Disease; Protein Aggregation, Pathological

Emerging evidence suggests that the SNP rs2736990 of SNCA is a susceptibility factor for idiopathic Parkinson's disease (PD) in different populations, but the studies which examined the association have provided inconsistent results. Therefore, we performed a meta-analysis of some case-control studies to obtain a more exact estimation of there associations. All the relevant studies were extracted from PubMed, Embase, EBSCO, Chineses national knowledge infrastructure, Google Scholar and Wanfang databases (up to February 2017). A total of six studies with 2525 PD cases and 2165 controls were eventually enrolled in the present meta-analysis based on the strict inclusion and exclusion criteria. The pooled analysis showed that there is a significant association between rs2736990 polymorphism and PD susceptibility in all genetic models (T vs. C: OR=0.772, 95%CI: 0.709-0.840, P=0.001; TT vs. CC: OR=0.586, 95%CI: 0.490-0.701, P=0.001; TC vs. CC: OR=0.814, 95%CI: 0.716-0.925, P=0.002; TT+TC vs. CC: OR=0.752, 95%CI: 0.666-0.848, P=0.001; TT vs. TC+CC: OR=0.658, 95%CI: 0.561-0.772, P=0.001). Our meta-analysis provides evidence that the T allele, TT and TC genotype of rs2736990(C/T) polymorphism may decrease the risk of PD.

Topics: alpha-Synuclein; Asian People; Case-Control Studies; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Parkinson Disease; Polymorphism, Genetic; Polymorphism, Single Nucleotide

Among the diseases affecting the central nervous system (CNS), neurodegenerations attract the interest of both the clinician and the medicinal chemist. The increasing average age of population, the growing number of patients, and the lack of long-term effective remedies push ahead the quest for novel tools against this class of pathologies. We present a review on the state of the art of the molecules (or combination of molecules) of natural origin that are currently under study against two well-defined pathologies: Parkinson's disease (PD) and Huntington's disease (HD). Nowadays, very few tools are available for preventing or counteracting the progression of such diseases. Two major parameters were considered for the preparation of this review: particular attention was reserved to these research works presenting well-defined molecular mechanisms for the studied compounds, and where available, papers reporting in vivo data were preferred. A literature search for peer-reviewed articles using PubMed, Scopus, and Reaxys databases was performed, exploiting different keywords and logical operators: 91 papers were considered (preferentially published after 2015). The review presents a brief overview on the etiology of the studied neurodegenerations and the current treatments, followed by a detailed discussion of the natural and semisynthetic compounds dividing them in different paragraphs considering their several mechanisms of action.

Topics: alpha-Synuclein; Animals; Anti-Dyskinesia Agents; Antioxidants; Antiparkinson Agents; Autophagy; Biological Products; Dementia; Dopamine; Drug Discovery; Drug Evaluation, Preclinical; Humans; Huntington Disease; Microglia; Mitochondria; Molecular Targeted Therapy; Monoamine Oxidase Inhibitors; Oxidative Stress; Parkinson Disease; Plant Preparations; Protein Aggregation, Pathological; Signal Transduction

Vaccination therapies constitute potential treatment options in neurodegenerative disorders such as Alzheimer disease or Parkinson disease. While a lot of research has been performed on vaccination against extracellular amyloid β, the focus recently shifted toward vaccination against the intracellular proteins tau and α-synuclein, with promising results in terms of protein accumulation reduction. In this review, we briefly summarize lessons to be learned from clinical vaccination trials in Alzheimer disease that target amyloid β. We then focus on tau and α-synuclein. For both proteins, we provide important data on protein immunogenicity, and put them into context with data available from both animals and human vaccination trials targeted at tau and α-synuclein. Together, we give a comprehensive overview about current clinical data, and discuss associated problems.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Parkinson Disease; Tauopathies; Vaccination

The accumulation of misfolded α-synuclein aggregates is associated with PD. However, the diagnostic value of the α-synuclein levels in CSF is still under investigation.. A comprehensive search of the literature was performed, yielding 34 studies eligible for meta-analysis. We included studies that reported data on CSF total, oligomeric and phosphorylated α-synuclein in patients with PD and healthy participants, neurological controls, or other parkinsonisms. Standardized mean differences were pooled using random-effects models, and heterogeneity was reported as I. Concentrations of α-synuclein species in PD did not show significant differences with respect to the levels found in other parkinsonisms. Total α-synuclein was significantly reduced in PD when compared with controls (standardized mean differences -0.48; P < .001, I. Most of the studies were at high risk of bias and have concerns regarding applicability. Diagnostic performance of CSF α-synuclein species is still below what would be considered acceptable for their introduction in clinical practice. Future research should focus on combining α-synuclein species with other biochemical markers as well on improving the standardization of current assays. © 2017 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Databases, Bibliographic; Humans; Parkinson Disease

The distinctive pathological hallmarks of Parkinson's disease are the progressive death of dopaminergic neurons and the intracellular accumulation of Lewy bodies enriched in α-synuclein protein. Several lines of evidence from the study of sporadic, familial and pharmacologically induced forms of human Parkinson's disease also suggest that mitochondrial dysfunction plays an important role in disease progression. Although many functions have been proposed for α-synuclein, emerging data from human and animal models of Parkinson's disease highlight a role for α-synuclein in the control of neuronal mitochondrial dynamics. Here, we review the α-synuclein structural, biophysical and biochemical properties that influence relevant mitochondrial dynamic processes such as fusion-fission, transport and clearance. Drawing on current evidence, we propose that α-synuclein contributes to the mitochondrial defects that are associated with the pathology of this common and progressive neurodegenerative disease.

Topics: alpha-Synuclein; Animals; Humans; Mitochondrial Dynamics; Mitophagy; Models, Biological; Parkinson Disease

Gaucher disease, the most common lysosomal storage disorder, is caused by mutations in the gene encoding the acid-β-glucosidase lysosomal hydrolase enzyme that cleaves glucocerebroside into glucose and ceramide. Reduced enzyme activity and impaired structural stability arise due to >300 known disease-causing mutations. Several of these mutations have also been associated with an increased risk of Parkinson disease (PD). Since the discovery of the acid-β-glucosidase X-ray structure, there have been major advances in our understanding of the structural properties of the protein. Analysis of specific residues has provided insight into their functional and structural importance and provided insight into the pathogenesis of Gaucher disease and the contribution to PD. Disease-causing mutations are positioned throughout the acid-β-glucosidase structure, with many located far from the active site and thus retaining some enzymatic activity however, thus far no clear relationship between mutation location and disease severity has been established. Here, we review the crystal structure of acid-β-glucosidase, while highlighting important structural aspects of the protein in detail. This review discusses the structural stability of acid-β-glucosidase, which can be altered by pH and glycosylation, and explores the relationship between known Gaucher disease and PD mutations, structural stability and disease severity.

Topics: alpha-Synuclein; Animals; Gaucher Disease; Glycosylation; Humans; Lysosomes; Mutation; Parkinson Disease

The motor deficits which characterise the sporadic form of Parkinson's disease arise from age-related loss of a subset of dopamine neurons in the substantia nigra. Although motor symptoms respond to dopamine replacement therapies, the underlying disease process remains. This review details some features of the progressive molecular pathology and proposes deployment of a combination of nutrients: R-lipoic acid, acetyl-l-carnitine, ubiquinol, melatonin (or receptor agonists) and vitamin D3, with the collective potential to slow progression of these features. The main nutrient targets include impaired mitochondria and the associated oxidative/nitrosative stress, calcium stress and impaired gene transcription induced by pathogenic forms of alpha- synuclein. Benefits may be achieved via nutrient influence on epigenetic signaling pathways governing transcription factors for mitochondrial biogenesis, antioxidant defences and the autophagy-lysosomal pathway, via regulation of the metabolic energy sensor AMP activated protein kinase (AMPK) and the mammalian target of rapamycin mTOR. Nutrients also benefit expression of the transcription factor for neuronal survival (NR4A2), trophic factors GDNF and BDNF, and age-related calcium signals. In addition a number of non-motor related dysfunctions in circadian control, clock genes and associated metabolic, endocrine and sleep-wake activity are briefly addressed, as are late-stage complications in respect of cognitive decline and osteoporosis. Analysis of the network of nutrient effects reveals how beneficial synergies may counter the accumulation and promote clearance of pathogenic alpha-synuclein.

Topics: alpha-Synuclein; Animals; Calcium Signaling; Chronobiology Disorders; Disease Management; Dopamine; Dopaminergic Neurons; Epigenesis, Genetic; Humans; Mitochondria; Parkinson Disease; Substantia Nigra

Starting two decades ago with the discoveries of genetic links between alpha-synuclein and Parkinson's disease risk and the identification of aggregated alpha-synuclein as the main protein constituent of Lewy pathology, alpha-synuclein has emerged as the major therapeutic target in Parkinson's disease and related synucleinopathies. Following the suggestion that alpha-synuclein pathology gradually spreads through the nervous system following a stereotypic pattern and the discovery that aggregated forms of alpha-synuclein can propagate pathology from one cell to another, and thereby probably aggravate existing deficits as well as generate additional symptoms, the idea that alpha-synuclein is a viable therapeutic target gained further support. In this review we describe current challenges and possibilities with alpha-synuclein as a therapeutic target. We briefly highlight gaps in the knowledge of the role of alpha-synuclein in disease, and propose that a deeper understanding of the pathobiology of alpha-synuclein can lead to improved therapeutic strategies. We describe several treatment approaches that are currently being tested in advanced animal experiments or already are in clinical trials. We have divided them into approaches that reduce alpha-synuclein production; inhibit alpha-synuclein aggregation inside cells; promote its degradation either inside or outside cells; and reduce its uptake by neighbouring cells following release from already affected neurons. Finally, we briefly discuss challenges related to the clinical testing of alpha-synuclein therapies, for example difficulties in monitoring target engagement and the need for relatively large trials of long duration. We conclude that alpha-synuclein remains one of the most compelling therapeutic targets for Parkinson's disease, and related synucleinopathies, and that the multitude of approaches being tested provides hope for the future.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Genetic Therapy; Humans; Multiple System Atrophy; Neurons; Parkinson Disease

In Parkinson's disease, intracellular α-synuclein inclusions form in neurons. We suggest that prion-like behavior of α-synuclein is a key component in Parkinson's disease pathogenesis. Although multiple molecular changes are involved in the triggering of the disease process, we propose that neuron-to-neuron transfer is a crucial event that is essential for Lewy pathology to spread from one brain region to another. In this review, we describe key findings in human postmortem brains, cultured cells, and animal models of disease that support the idea that α-synuclein can act as a prion. We consider potential triggers of the α-synuclein misfolding and why the aggregates escape cellular degradation under disease conditions. We also discuss whether different strains of α-synuclein fibrils can underlie differences in cellular and regional distribution of aggregates in different synucleinopathies. Our conclusion is that α-synuclein probably acts as a prion in human diseases, and a deeper understanding of this step in the pathogenesis of Parkinson's disease can facilitate the development of disease-modifying therapies in the future.

Topics: alpha-Synuclein; Humans; Parkinson Disease; Prion Diseases; Prions

Parkinson's disease (PD) is the most prevalent central nervous system (CNS) movement disorder and the second most common neurodegenerative disease overall. PD is characterized by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) within the midbrain, accumulation of alpha-synuclein (α-SYN) in Lewy bodies and neurites and excessive neuroinflammation. The neurodegenerative processes typically begin decades before the appearance of clinical symptoms. Therefore, the diagnosis is achievable only when the majority of the relevant DAergic neurons have already died and for that reason available treatments are only palliative at best. The causes and mechanism(s) of this devastating disease are ill-defined but complex interactions between genetic susceptibility and environmental factors are considered major contributors to the etiology of PD. In addition to the role of classical gene mutations in PD, the importance of regulatory elements modulating gene expression has been increasingly recognized. One example is the critical role played by microRNAs (miRNAs) in the development and homeostasis of distinct populations of neurons within the CNS and, in particular, in the context of PD. Recent reports demonstrate how distinct miRNAs are involved in the regulation of PD genes, whereas profiling approaches are unveiling variations in the abundance of certain miRNAs possibly relevant either to the onset or to the progression of the disease. In this review, we provide an overview of the miRNAs recently found to be implicated in PD etiology, with particular focus on their potential relevance as PD biomarkers, as well as their possible use in PD targeted therapy.

Topics: alpha-Synuclein; Antagomirs; Biomarkers; Exosomes; Humans; MicroRNAs; Neuroprotective Agents; Parkinson Disease; Protein Deglycase DJ-1; Ubiquitin-Protein Ligases

Alzheimer's and Parkinson's diseases are the most prevalent neurodegenerative diseases that generate important health-related direct and indirect socio-economic costs. They are characterized by severe neuronal losses in several disease-specific brain regions associated with deposits of aggregated proteins. In Alzheimer's disease, β-amyloid peptide-containing plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein tau are the two main neuropathological lesions, while Parkinson's disease is defined by the presence of Lewy Bodies that are intraneuronal proteinaceous cytoplasmic inclusions. α-Synuclein has been identified as a major protein component of Lewy Bodies and heavily implicated in the pathogenesis of Parkinson's disease. In the past few years, evidence has emerged to explain how these aggregate-prone proteins can undergo spontaneous self-aggregation, propagate from cell to cell, and mediate neurotoxicity. Current research now indicates that oligomeric forms are probably the toxic species. This article discusses recent progress in the understanding of the pathogenesis of these diseases, with a focus on the underlying mechanisms of protein aggregation, and emphasizes the pathophysiological molecular mechanisms leading to cellular toxicity. Finally, we present the putative direct link between β-amyloid peptide and tau in causing toxicity in Alzheimer's disease as well as α-synuclein in Parkinson's disease, along with some of the most promising therapeutic strategies currently in development for those incurable neurodegenerative disorders.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Humans; Nerve Degeneration; Neurodegenerative Diseases; Parkinson Disease; Protein Aggregation, Pathological; Tauopathies

Parkinson's disease (PD) is one of the most common progressive neurodegenerative disorders in modern society. The disease involves many genetic risk factors as well as a sporadic pathogenesis that is age- and environment-dependent. Of particular interest is the formation of intra-neural fibrillar aggregates, namely Lewy bodies (LBs), the histological hallmark of PD, which results from aberrant protein homeostasis or misfolding that results in neurotoxicity. A better understanding of the molecular mechanism and composition of these cellular inclusions will help shed light on the progression of misfolding-associated neurodegenerative disorders. Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is found to co-aggregate with α-synuclein (αS), the major component of LBs. Several familial mutations of UCH-L1, namely p.Ile93Met (p.I93M), p.Glu7Ala (p.E7A), and p.Ser18Tyr (p.S18Y), are associated with PD and other neurodegenerative disorders. Here, we review recent progress and recapitulate the impact of PD-associated mutations of UCH-L1 in the context of their biological functions gleaned from biochemical and biophysical studies. Finally, we summarize the effect of these genetic mutations and post-translational modifications on the association of UCHL1 and PD in terms of loss of cellular functions or gain of cellular toxicity.

Topics: Aged; alpha-Synuclein; Amino Acid Sequence; Disease Progression; Gene Expression; Humans; Lewy Bodies; Models, Molecular; Mutation; Parkinson Disease; Protein Domains; Protein Folding; Protein Processing, Post-Translational; Protein Structure, Secondary; Ubiquitin Thiolesterase; Ubiquitination

Mutations in LRRK2 comprise the most common cause for familial Parkinson's disease (PD), and variations increase risk for sporadic disease, implicating LRRK2 in the entire disease spectrum. LRRK2 is a large protein harbouring both GTPase and kinase domains which display measurable catalytic activity. Most pathogenic mutations increase the kinase activity, with increased activity being cytotoxic under certain conditions. These findings have spurred great interest in drug development approaches, and various specific LRRK2 kinase inhibitors have been developed. However, LRRK2 is a largely ubiquitously expressed protein, and inhibiting its function in some non-neuronal tissues has raised safety liability issues for kinase inhibitor approaches. Therefore, understanding the cellular and cell type-specific role(s) of LRRK2 has become of paramount importance. This review will highlight current knowledge on the precise biochemical activities of normal and pathogenic LRRK2, and highlight the most common proposed cellular roles so as to gain a better understanding of the cell type-specific effects of LRRK2 modulators.

Topics: alpha-Synuclein; Aminopyridines; Antiparkinson Agents; Autophagy; Benzamides; Endocytosis; Gene Expression; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Neurons; Parkinson Disease; Protein Domains; Protein Kinase Inhibitors; rab GTP-Binding Proteins; rab1 GTP-Binding Proteins; rab7 GTP-Binding Proteins

Gaucher disease is an autosomal recessive lysosomal storage disorder, caused by mutations in the GBA gene. The frequency of Gaucher disease patients and heterozygote carriers that developed Parkinson disease has been found to be above that of the control population. This fact suggests that mutations in the GBA gene can be involved in Parkison's etiology. Analysis of large cohorts of patients with Parkinson disease has shown that there are significantly more cases bearing GBA mutations than those found among healthy individuals. Functional studies have proven an interaction between α-synuclein and GBA, the levels of which presented an inverse correlation. Mutant GBA proteins cause increases in α-synuclein levels, while an inhibition of GBA by α-synuclein has been also demonstrated. Saposin C, a coactivator of GBA, has been shown to protect GBA from this inhibition. Among the GBA variants associated with Parkinson disease, E326K seems to be one of the most prevalent. Interestingly, it is involved in Gaucher disease only when it forms part of a double-mutant allele, usually with the L444P mutation. Structural analyses have revealed that both residues (E326 and L444) interact with Saposin C and, probably, also with α-synuclein. This could explain the antagonistic role of these two proteins in relation to GBA.

Topics: Alleles; alpha-Synuclein; Gaucher Disease; Gene Expression; Gene Frequency; Glucosylceramidase; Humans; Lysosomes; Mutation; Parkinson Disease; Saposins

α-Synuclein (α-Syn) aggregation is directly associated with Parkinson's disease (PD) pathogenesis. In vitro aggregation and in vivo animal model studies of α-Syn recapitulate many features of the disease pathogenesis. Six familial PD associated mutations of α-Syn have been discovered; many of which are associated with early onset PD. Three of PD associated mutations have been shown to accelerate the α-Syn aggregation, whereas other three are shown to delay the aggregation kinetics. The membrane binding studies also suggest that few of these PD mutants strongly bind to synthetic membrane vesicles, while others are shown to have attenuated membrane binding ability. Furthermore, the PD mutations do not drastically alter the toxicity of α-Syn oligomers/fibrils. Although according to recent suggestions that early formed oligomers are the most potent toxic species responsible for PD, only p.A30P mutant is shown to form faster oligomers and delayed conversion from oligomers to fibrils. Therefore, it is difficult to establish a unifying mechanism of how familial PD associated mutations affect the α-Syn structure, aggregation and function for their disease association. It is possible that each PD associated mutation alters α-Syn biology in a unique way, which might be responsible for disease pathogenesis. In this review, we discuss the structure function of α- Syn and how these are altered due to the PD associated mutations and their relationship to disease pathogenesis.

Topics: alpha-Synuclein; Amino Acid Sequence; Animals; Cell Membrane; Gene Expression; Humans; Mutation; Neurons; Parkinson Disease; Protein Aggregates; Protein Aggregation, Pathological; Protein Binding; Structure-Activity Relationship

Diagnosis of Parkinson's disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow early and more precise diagnosis and monitoring of dopamine replacement strategies and disease modifying treatments. Developments in analytical chemistry allow the detection of large numbers of molecules in plasma or cerebrospinal fluid, associated with the pathophysiology or pathogenesis of PD. This systematic review includes cerebrospinal fluid biomarker studies focusing on different disease pathways: oxidative stress, neuroinflammation, lysosomal dysfunction and proteins involved in PD and other neurodegenerative disorders, focusing on four clinical domains: their ability to (1) distinguish PD from healthy subjects and other neurodegenerative disorders as well as their relation to (2) disease duration after initial diagnosis, (3) severity of disease (motor symptoms) and (4) cognitive dysfunction. Oligomeric alpha-synuclein might be helpful in the separation of PD from controls. Through metabolomics, changes in purine and tryptophan metabolism have been discovered in patients with PD. Neurofilament light chain (NfL) has a significant role in distinguishing PD from other neurodegenerative diseases. Several oxidative stress markers are related to disease severity, with the antioxidant urate also having a prognostic value in terms of disease severity. Increased levels of amyloid and tau-proteins correlate with cognitive decline and may have prognostic value for cognitive deficits in PD. In the future, larger longitudinal studies, corroborating previous research on viable biomarker candidates or using metabolomics identifying a vast amount of potential biomarkers, could be a good approach.

Topics: alpha-Synuclein; Biomarkers; Humans; Parkinson Disease; tau Proteins

As a key regulator of cell metabolism and survival, mechanistic target of rapamycin (mTOR) emerges as a novel therapeutic target for Parkinson's disease (PD). A growing body of research indicates that restoring perturbed mTOR signaling in PD models can prevent neuronal cell death. Nevertheless, molecular mechanisms underlying mTOR-mediated effects in PD have not been fully understood yet. Here, we review recent progress in characterizing the association of mTOR signaling with PD risk factors and further discuss the potential roles of mTOR in PD.

Topics: alpha-Synuclein; Animals; Apoptosis; Autophagy; Dopaminergic Neurons; Genetic Predisposition to Disease; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Nerve Tissue Proteins; Neurotoxins; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Risk Factors; Signal Transduction; TOR Serine-Threonine Kinases

A common pathological event among various neurodegenerative disorders (NDs) is the misfolding and aggregation of different proteins in the brain. This is thought to potentiate aberrant protein-protein interactions that culminate in the disruption of several biological processes and, ultimately, in neuronal cell loss. Although protein aggregates are a common hallmark in several disorders, the molecular pathways leading to their generation remain unclear. The misfolding and aggregation of α-Synuclein (aSyn) is the pathological hallmark of Parkinson disease (PD), the second most common age related ND. It has been postulated that oligomeric species of aSyn, rather than more mature aggregated forms of the protein, are the causative agents of cytotoxicity. In recent years, we have been investigating the molecular mechanisms underlying the initial steps of aSyn accumulation in living cells. Using an unbiased genome-wide lentiviral RNAi screen we identified trafficking and kinase genes as modulators of aSyn oligomerization, aggregation, and toxicity. Among those, Rab8b, Rab11a, Rab13 and Slp5 were found to promote the clearance of aSyn inclusions and reduce aSyn toxicity. Moreover, we found that endocytic recycling and secretion of aSyn was enhanced upon expression of Rab11a or Rab13 in cells accumulating aSyn inclusions. Altogether, our findings suggest specific trafficking steps may prove beneficial as targets for therapeutic intervention in synucleinopathies, and should be further investigated in other models.

Topics: alpha-Synuclein; Animals; Humans; Parkinson Disease; Protein Aggregates; Protein Transport

Parkinson's disease (PD) is the most common movement disorder associated with the elderly which, other than symptomatic therapies, has no effective treatment or preventive measures. Sirtuins and their pharmacological activators/inhibitors have been associated with a range of neuroprotective effects, and a large body of work on sirtuins' influence on PD pathology has accumulated over the past decade. Here, evidence for sirtuins' activities as modifiers of PD pathology and how the mammalian sirtuin paralogues may have conflicting impacts on PD pathogenesis and disease progression is reviewed. The possible cellular and molecular mechanisms underlying sirtuin activities in PD are discussed in the light of current knowledge with reference to autophagy, mitochondrial homeostasis, and microtubule dynamics. © 2016 Wiley Periodicals, Inc.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Enzyme Activators; Humans; Neurons; Neuroprotective Agents; Parkinson Disease; Sirtuins

Exosomes play a key role in delivery of various biological material and complex signals from one cell to another at long distances. These small extracellular vehicles are involved in mediating multiple physiological and pathogenic processes. In neurodegenerative diseases such as Parkinson's disease (PD), exosomes contribute to disease propagation through transferring misfolded proteins from affected cells to normal cells. In PD, progressive degeneration of neurons arises from the extensive accumulation of toxic forms of α-synuclein in the cytoplasm. α-Synuclein could exist in several forms, some of which (i.e., oligomeric and polymeric forms) are cytotoxic. Neuron-derived exosomes were found to transfer α-synuclein toxic forms between neuronal and non-neuronal cells (such as astrocytes and microglia) thereby contributing to PD spreading. Deposition of α-synuclein in glial cells induces inflammation that could be further propagated to other glial cells and neurons. Neuroinflammation promotes degeneration of neurons and aggravates the pathogenesis of PD.

Topics: alpha-Synuclein; Animals; Exosomes; Humans; Nerve Degeneration; Parkinson Disease

Protein misfolding under stressful environmental conditions cause several cellular problems owing to the disturbed cellular protein homeostasis, which may further lead to neurological disorders like Parkinson's disease (PD), Alzheimer's disease (AD), Amyloid lateral sclerosis and Huntington disease (HD). The presence of cellular defense mechanisms like molecular chaperones and proteasomal degradation systems prevent protein misfolding and aggregation. Molecular chaperones plays primary role in preventing protein misfolding by mediating proper native folding, unfolding and refolding of the polypeptides along with vast number of cellular functions. In past few years, the understanding of molecular chaperone mechanisms has been expanded enormously although implementation to prevent protein aggregation diseases is still deficient. We in this review evaluated major classes of molecular chaperones and their mechanisms relevant for preventing protein aggregation, specific case of α-synuclein aggregation. We also evaluate the molecular chaperone function as a novel therapeutic approach and the chaperone inhibitors or activators as small molecular drug targets.

Topics: alpha-Synuclein; Animals; Heat-Shock Proteins; Humans; Parkinson Disease; Protein Aggregation, Pathological; Protein Folding; Proteostasis Deficiencies

Parkinson's disease (PD) is a neurological disorder marked by the presence of cytoplasmic inclusions, Lewy bodies (LBs) and Lewy neurites (LNs) as well as the degeneration of dopamine producing neurons in the substantia nigra region of the brain. The LBs and LNs in PD are mainly composed of aggregated form of a presynaptic protein, α-synuclein (α-Syn). However, the mechanisms of α-Syn aggregation and actual aggregated species responsible for the degeneration of dopaminergic neurons have not yet been resolved. Despite the fact that α-Syn aggregation in LBs and LNs is crucial and mutations of α-Syn are associated with early onset PD, it is really a challenging task to establish a correlation between α-Syn aggregation rate and PD pathogenesis. Regardless of strong genetic contribution, PD is mostly sporadic and familial forms of the disease represent only a minor part (<10%) of all cases. The complexity in PD further increases due to the involvement of several cellular factors in the pathogenesis of the disease as well as the environmental factors associated with the risk of developing PD. Therefore, effect of these factors on α-Syn aggregation pathway and how these factors modulate the properties of wild type (WT) as well as mutated α-Syn should be collectively taken into account. The present review specifically provides an overview of recent research on α-Syn aggregation pathways and its modulation by several cellular factors potentially relevant to PD pathogenesis. We also briefly discuss about effect of environmental risk factors on α-Syn aggregation.

Topics: alpha-Synuclein; Amino Acid Sequence; Animals; Glycosaminoglycans; Humans; Parkinson Disease; Polyamines; Protein Aggregates

Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA) are three major synucleinopathies characterized by α-synuclein-containing inclusions in the brains of patients. Because the cell types and brain structures that are affected vary markedly between the disorders, the patients have different clinical manifestations in addition to some overlapping symptoms, which are the basis for differential diagnosis. Cognitive impairment and depression associated with hippocampal dysfunction are frequently observed in these disorders. While various α-synuclein-containing inclusions are found in the hippocampal formation, increasing evidence supports that small α-synuclein aggregates or oligomers may be the real culprit, causing deficits in neurotransmission and neurogenesis in the hippocampus and related brain regions, which constitute the major mechanism for the hippocampal dysfunctions and associated neuropsychiatric manifestations in synucleinopathies.

Topics: alpha-Synuclein; Animals; Hippocampus; Humans; Inclusion Bodies; Lewy Body Disease; Multiple System Atrophy; Neurogenesis; Parkinson Disease; Protein Aggregates; Protein Aggregation, Pathological; Synaptic Transmission

Abnormal deposition of α-synuclein (ASN) is a hallmark and possible central mechanism of Parkinson's disease and other synucleinopathies. Their therapy is currently hampered by the lack of early, screening-compatible diagnostic methods and efficient treatments. Areas covered: Patent applications related to synucleinopathies obtained from Patentscope and Espacenet databases are described against the background of current knowledge regarding the regulatory mechanisms of ASN behavior including alternative splicing, post-translational modifications, molecular interactions, aggregation, degradation, and changes in localization. Expert opinion: As the central pathological feature and possibly one of root causes in a number of neurodegenerative diseases, deregulation of ASN is a potentially optimal diagnostic and therapeutic target. Changes in total ASN may have diagnostic value, especially if non-invasive /peripheral tissue tests can be developed. Targeting the whole ASN pool for therapeutic purposes may be problematic, however. ASN mutations, truncation, and post-translational modifications have great potential value; therapeutic approaches selective towards aggregated or aggregation-prone ASN forms may lead to more successful and safe treatments. Numerous ASN interactions with signaling pathways, protein degradation and stress mechanisms widen its potential therapeutic significance dramatically. However, significant improvement in the basic knowledge on ASN is necessary to fully exploit these opportunities.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Drug Design; Humans; Neurodegenerative Diseases; Parkinson Disease; Patents as Topic; Signal Transduction

Initial clinical recognition of "paralysis agitans" by James Parkinson was expanded by Jean-Martin Charcot, who recognized additional clinical findings of his own, such as slowness (distinct from paralysis), rigidity (distinct from spasticity) and characteristic countenance. Charcot assembled these findings under the umbrella of "Parkinson disease (PD)". This purely clinical concept was so prescient and penetrating that subsequent neuropathological and biochemical evidences were ordered along this axis to establish the nigra-central trinity of PD (dopamine depletion, nigral lesion with Lewy bodies: LBs). Although dramatic efficacy of levodopa boosted an enthusiasm for this nigra-centralism, extranigral lesions were identified, especially after identification of alpha-synuclein (αS) as a major constituent of LBs. Frequent αS lesions in the lower brainstem with their presumed upward spread were coupled with the self-propagating property of αS molecule, as a molecular template, to constitute the prion-Braak hypothesis. This hybrid concept might expectedly explain clinical, structural and biochemical features of PD/dementia with Lewy bodies (DLB) as if they were stereotypic. In spite of this ordered explanation, recent studies have demonstrated unexpectedly that αS lesions in the human brain, as well as their corresponding clinical manifestations, are much more disordered. Even with such a chaos of LB disorders, affected neuronal groups are uniformly characterized by hyperbranching axons, which may facilitate distal-dominant degeneration and retrograde progression of LB-related degeneration along axons as a fundamental structural order to template LB disorders. This "structural template" hypothesis may explain why: (i) some selective groups are prone to develop Lewy pathology; (ii) their clinical manifestations (especially non-motor components) are vague and generalized without somatotopic accentuation; (iii) distal axons and terminals are preferentially affected early, which is clinically detectable as reduced myocardial uptake of meta-iodobenzylguanidine in PD/DLB. Because each Lewy-prone system develops LBs independently, their isolated presentation as "focal LB disease" or their whatever combinations as "multifocal LB disease" are a more plausible framework to explain clinicopathological diversities of LB disorders. Clinical criteria are now being revised to integrate these clinicopathological disorders of PD/DLB. To gain closer access to the reality of t

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Axons; Brain; Disease Progression; Female; Humans; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Retrograde Degeneration; Substantia Nigra

Parkinson's disease (PD) is characterized by α-synuclein accumulation, dopaminergic neuron loss and inflammation. α-Synuclein can be secreted by neurons and activate microglia to different degrees. Excessive microglial activation can increase the production of tumor necrosis factor alpha (TNF-α), interleukin-1-β (IL-1β), interleukin-6 (IL-6), interferon-γ (INF-γ), inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS) and nitric oxide (NO), and can also enhance microglial phagocytosis and migration as well as lymphocyte infiltration. Pathological α-synuclein and microglial activation can potentiate each other, leading to the loss of dopaminergic neurons and accelerated PD degeneration. This review will mainly describe the profiles of α-synuclein-activated microglia, with particular emphasis on the signaling cascades involved in this process.

Topics: alpha-Synuclein; Disease Progression; Dopaminergic Neurons; Humans; Microglia; Neuroimmunomodulation; Oxidative Stress; Parkinson Disease; Phagocytosis; Signal Transduction

Parkinson's disease (PD), the second most common progressive neurodegenerative disorder of aging, was long believed to be a non-genetic sporadic origin syndrome. The proof that several genetic loci are responsible for rare Mendelian forms has represented a revolutionary breakthrough, enabling to reveal molecular mechanisms underlying this debilitating still incurable condition. While single nucleotide polymorphisms (SNPs) and small indels constitute the most commonly investigated DNA variations accounting for only a limited number of PD cases, larger genomic molecular rearrangements have emerged as significant PD-causing mutations, including submicroscopic Copy Number Variations (CNVs). CNVs constitute a prevalent source of genomic variations and substantially participate in each individual's genomic makeup and phenotypic outcome. However, the majority of genetic studies have focused their attention on single candidate-gene mutations or on common variants reaching a significant statistical level of acceptance. This gene-centric approach is insufficient to uncover the genetic background of polygenic multifactorial disorders like PD, and potentially masks rare individual CNVs that all together might contribute to disease development or progression. In this review, we will discuss literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will analyze the most frequent copy number changes in familiar PD genes and provide a "systems biology" overview of rare individual rearrangements that could functionally act on commonly deregulated molecular pathways. Assessing the global genome-wide burden of CNVs in PD patients may reveal new disease-related molecular mechanisms, and open the window to a new possible genetic scenario in the unsolved PD puzzle.

Topics: alpha-Synuclein; Chromosome Deletion; DNA Copy Number Variations; Genetic Loci; Genome, Human; Genomics; Humans; Parkinson Disease; Polymorphism, Single Nucleotide; Protein Deglycase DJ-1; Proton-Translocating ATPases; Systems Biology; Ubiquitin-Protein Ligases

Prion-like propagation of abnormal intracytoplasmic proteins, which are the defining features of major neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), has been proposed. A growing body of evidence strongly suggests that abnormal tau, α-synuclein and TDP-43 have prion-like properties, convert the corresponding normal proteins into abnormal forms, and are transmitted from cell to cell, spreading throughout the brain. This idea is extremely important not only for understanding the pathogenesis and progression of these diseases, but also for the development of molecular therapies. Since the distributions and spreading of the abnormal proteins are closely associated with disease symptoms and progression, gain-of-toxic-function of these proteins may affect the neurons and glial cells either directly or indirectly, or both. It is essential to regulate the aggregation of abnormal intracellular proteins and their cell-to-cell transmission in order to stop, or at least slow, the progression of these diseases.

Topics: alpha-Synuclein; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Disease Progression; DNA-Binding Proteins; Humans; Neurodegenerative Diseases; Parkinson Disease; Prions; tau Proteins

Parkinson's disease is the second most common neurodegenerative disorder, with only partial symptomatic therapy and no mechanism-based therapies. The accumulation and aggregation of α-synuclein is causatively linked to the sporadic form of the disease, which accounts for 95% of cases. The pathology is a result of a gain of toxic function of misfolded α-synuclein conformers, which can template the aggregation of soluble monomers and lead to cellular dysfunction, at least partly by interfering with membrane fusion events at synaptic terminals. Here, we discuss the transcellular propagation and intracellular trafficking of α-synuclein and posit that endosomal processing could be a point of convergence between these two routes. Understanding these events will clarify the therapeutic potential of enzymes that regulate protein trafficking and degradation in synucleinopathies.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Humans; Parkinson Disease; Protein Transport; SNARE Proteins

Lewy bodies and Lewy neurites composed primarily of α-synuclein characterize synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Despite decades of research on the impact of α-synuclein, little is known how abnormal inclusion made of this protein compromise neuronal function. Emerging evidence suggests that defects in axonal transport caused by aggregated α-synuclein contribute to neuronal dysfunction. These defects appear to occur well before the onset of neuronal death. Susceptible neurons in PD such as dopamine neurons with long elaborate axons may be particularly sensitive to abnormal axonal transport. Axonal transport is critical for delivery of signaling molecules to the soma responsible for neuronal differentiation and survival. In addition, axonal transport delivers degradative organelles such as endosomes and autophagosomes to lysosomes located in the soma to degrade damaged proteins and organelles. Identifying the molecular mechanisms by which axonal transport is impaired in PD and DLB may help identify novel therapeutic targets to enhance neuron survival and even possibly prevent disease progression. Here, we review the evidence that axonal transport is impaired in synucleinopathies, and describe potential mechanisms by which contribute to these defects.

Topics: alpha-Synuclein; Animals; Axonal Transport; Humans; Lewy Body Disease; Parkinson Disease

Lysosomal transport of cargos in neurons is essential for neuronal proteostasis, transmission and functional motors and behaviours. Lysosomal malfunction including storage disorders is involved in the pathogenesis of Parkinson's disease (PD). Given the unclear molecular mechanisms of diverse defects in PD phenotypes, especially behavioural deficits, this mini review explores the cellular contexts of PD impulse control disorders and the molecular aspects of lysosomal cross-membrane transports. Focuses are paid to trace metal involvements in α-synuclein assembly in Lewy bodies, the functions and molecular interactions of ATP13A2 as ATPase transporters in lysosomal membranes for cross-membrane trafficking and lysosomal homeostasis, and our current understandings of the neural circuits in ICD. Erroneously polarized distributions of cargos such as metals and lipids on each side of lysosomal membranes triggered by gene mutations and deregulated expression of ATP13A2 may thus instigate sensing protein structural changes such as aggregations, organelle degeneration, and specific neuronal ageing and death in Parkinsonism.

Topics: alpha-Synuclein; Animals; Disruptive, Impulse Control, and Conduct Disorders; Humans; Intracellular Membranes; Lewy Bodies; Lysosomes; Manganese; Neurons; Parkinson Disease; Protein Transport; Proton-Translocating ATPases

The neuropathological hallmark of Parkinson disease (PD) is abnormal accumulation of α-synuclein (α-syn). Demonstrating pathological α-syn in live patients would be useful for identifying and monitoring PD patients. To date, however, imaging and biofluid approaches have not permitted premortem assessment of pathological α-syn. α-syn pathology in the peripheral nervous system of patients with PD has been demonstrated in studies dating back more than 40 years. More recent work suggests that colon, submandibular gland and skin biopsies could be useful as expedient biomarkers but histological differentiation of pathological and normal peripheral α-syn has been challenging and multiple research groups have reported variable results. A variety of immunohistochemical methods have been employed but almost all studies to date originated at single centers with no independent, blinded replication. To address these issues, the Michael J. Fox Foundation for Parkinson's Research sponsored a series of meetings and investigations by several research groups with relevant experience. The major finding reported herein was that biopsies can be used to distinguish PD patients from normal subjects. However, full assessment of the clinical potential of biopsy will only be achieved through large, multicenter trials in which both the initial detection methodology and histology have been assessed by blinded panels of pathologists.

Topics: alpha-Synuclein; Biomarkers; Biopsy; Colon; Congresses as Topic; Humans; Parkinson Disease; Skin; Submandibular Gland

Symptoms of Parkinson's disease arise due to neuronal loss in multiple brain regions, especially dopaminergic neurons in the substantia nigra pars compacta. Current therapies aim to restore dopamine levels in the brain, but while these provide symptomatic benefit, they do not prevent ongoing neurodegeneration. Preventing neuronal death is a major strategy for disease-modifying therapies; however, while many pathogenic factors have been identified, it is currently unknown how neurons die in the disease. Ferroptosis, a recently identified iron-dependent cell death pathway, involves several molecular events that have previously been implicated in PD. This review will discuss ferroptosis and other cell death pathways implicated in PD neurodegeneration, with a focus on the potential to therapeutically target these pathways to slow the progression of this disease.

Topics: alpha-Synuclein; Animals; Brain; Cell Death; Dopaminergic Neurons; Glutathione; Parkinson Disease

Intracellular α-synuclein (α-syn)-rich protein aggregates called Lewy pathology (LP) and neuronal death are commonly found in the brains of patients with clinical Parkinson disease (cPD). It is widely believed that LP appears early in the disease and spreads in synaptically coupled brain networks, driving neuronal dysfunction and death. However, post-mortem analysis of human brains and connectome-mapping studies show that the pattern of LP in cPD is not consistent with this simple model, arguing that, if LP propagates in cPD, it must be gated by cell- or region-autonomous mechanisms. Moreover, the correlation between LP and neuronal death is weak. In this Review, we briefly discuss the evidence for and against the spreading LP model, as well as evidence that cell-autonomous factors govern both α-syn pathology and neuronal death.

Topics: alpha-Synuclein; Animals; Brain; Cell Death; Humans; Lewy Bodies; Neurons; Parkinson Disease

Synaptopathies are diseases with synapse defects as shared pathogenic features, encompassing neurodegenerative disorders such as Parkinson's disease (PD). In sporadic PD, the most common age-related neurodegenerative movement disorder, nigrostriatal dopaminergic deficits are responsible for the onset of motor symptoms that have been related to

Topics: alpha-Synuclein; Animals; Brain; Dopaminergic Neurons; Humans; Neurons; Parkinson Disease; Synapses

Current therapies for Parkinson's disease (PD) confer symptomatic relief and are particularly efficient in the treatment of motor symptoms in earlier disease stages. However, we are still unable to treat the causes of neurodegeneration by modification of the underlying mechanisms, which is partially due to their insufficient understanding. In this short review, we focus on two pivotal disease mechanisms: alpha-synuclein pathology and dysfunction of iron homeostasis as well as their intricate interaction. Both pathomechanisms have been extensively studied in the past and represent valid targets for disease-modifying pharmacological treatment approaches for PD. We summarize the current attempts to exploit iron chelation and modification of alpha-synuclein pathology as translational therapies in PD and discuss the chances and challenges of prospective disease-modifying approaches.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Humans; Iron; Parkinson Disease

Alterations in α-synuclein dosage lead to familial Parkinson's disease (PD), and its accumulation results in synucleinopathies that include PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Furthermore, α-synuclein contributes to the fibrilization of amyloid-b and tau, two key proteins in Alzheimer's disease, which suggests a central role for α-synuclein toxicity in neurodegeneration. Recent studies of factors contributing to α-synuclein toxicity and its disruption of downstream cellular pathways have expanded our understanding of disease pathogenesis in synucleinopathies. In this Review, we discuss these emerging themes, including the contributions of aging, selective vulnerability and non-cell-autonomous factors such as α-synuclein cell-to-cell propagation and neuroinflammation. Finally, we summarize recent efforts toward the development of targeted therapies for PD and related synucleinopathies.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Autophagy; Axonal Transport; Endoplasmic Reticulum; Golgi Apparatus; Humans; Lewy Body Disease; Lysosomes; Mitochondria; Molecular Targeted Therapy; Multiple System Atrophy; Neurons; Parkinson Disease; Protein Aggregates; Protein Aggregation, Pathological; Synapses; tau Proteins

Parkinson's disease (PD) is a frequent neurodegenerative disease with a premotor phase that lasts several years. Risk factors that have been linked to PD are tobacco, caffeine, black tea, pesticides and calcium channel blockers. Some risk factors may be due to inverse causality (e.g. changes in personality during the premotor phase). The genetics of PD are complex with a contribution of Mendelian (e.g. SNCA, LRRK2, Parkin, Pink1,…) and non-Mendelian factors (e.g. single nucleotide polymorphisms). Glucocerebrosidase gene mutations (Gaucher disease) are currently the strongest genetic risk factor for PD. Studying risk factors will help to better understand the pathogenesis of PD.

Topics: Age Distribution; Age of Onset; alpha-Synuclein; Caffeine; Causality; Gene-Environment Interaction; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Mutation; Oxidative Stress; Parkinson Disease; Pesticides; Polymorphism, Single Nucleotide; Prevalence; Risk Factors; Sex Distribution; Smoking; Uric Acid

A wide variety of different functions and an impressive array of interactors have been associated with leucine-rich repeat kinase 2 (LRRK2) over the years. Here, I discuss the hypothesis that LRRK2 may be capable of interacting with different proteins at different times and places, therefore, controlling a plethora of diverse functions based on the different complexes formed. Among these, I will then focus on macroautophagy in the general context of the endolysosomal system. First, the relevance of autophagy in Parkinson's disease will be evaluated giving a brief overview of all the relevant Parkinson's disease genes; then, the association of LRRK2 with macroautophagy and the endolysosomal pathway will be analyzed based on the supporting literature.

Topics: alpha-Synuclein; Autophagy; Endosomes; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lysosomes; Models, Biological; Mutation; Parkinson Disease; Protein Binding; Signal Transduction; Vesicular Transport Proteins

Currently, treatment of Parkinson's disease aims at alleviating its symptoms. However development of disease-modifying drugs has been a remarkable advancement in recent years. Furthermore, clinical trials of immunotherapy against α-synuclein, a protein involved in the pathogenesis of and lesion expansion in Parkinson's disease, have been initiated. Here, the disease-modifying treatment for patients with Parkinson's disease including the current α-synuclein immunotherapy, gene therapy, protein injection therapy, and cell transplantation therapy, has been reviewed.

Topics: alpha-Synuclein; Brain; Cell- and Tissue-Based Therapy; Genetic Therapy; Humans; Immunotherapy; Parkinson Disease

Intracellular aggregates of the α-synuclein protein result in cell loss and dysfunction in Parkinson's disease and atypical Parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as α-synucleinopathies, may be characterized by a different suite of molecular triggers that initiate pathogenesis. The mechanisms whereby α-synuclein aggregates mediate cytotoxicity also remain to be fully elucidated. However, recent studies have implicated the cell-to-cell spread of α-synuclein as the major mode of disease propagation between brain regions during disease progression. Here, we review the current evidence for different modes of α-synuclein cellular release, movement and uptake, including exocytosis, exosomes, tunneling nanotubes, glymphatic flow and endocytosis. A more detailed understanding of the major modes by which α-synuclein pathology spreads throughout the brain may provide new targets for therapies that halt the progression of disease.

Topics: alpha-Synuclein; Animals; Astrocytes; Cell Communication; Exosomes; Extracellular Space; Humans; Intracellular Space; Lewy Bodies; Lewy Body Disease; Microglia; Models, Biological; Multiple System Atrophy; Parkinson Disease; Protein Aggregation, Pathological; Protein Binding; Protein Transport

Both Parkinson's disease (PD) and stroke are debilitating conditions that result in neuronal death and loss of neurological functions. These two conditions predominantly affect aging populations with the deterioration of the quality of life for the patients themselves and a tremendous burden to families. While the neurodegeneration and symptomology of PD develop chronically over the years, post-stroke neuronal death and dysfunction develop rapidly in days. Despite the discrepancy in the pathophysiological time frame and severity, both conditions share common molecular mechanisms that include oxidative stress, mitochondrial dysfunction, inflammation, endoplasmic reticulum stress, and activation of various cell death pathways (apoptosis/necrosis/autophagy) that synergistically modulate the neuronal death. Emerging evidence indicates that several proteins associated with early-onset familial PD play critical roles in mediating the neuronal death. Importantly, mutations in the genes encoding Parkin, PTEN-induced putative kinase 1 and DJ-1 mediate autosomal recessive forms of PD, whereas mutations in the genes encoding leucine-rich repeat kinase 2 and α-synuclein are responsible for autosomal dominant PD. This review discusses the significance of these proteins with the emphasis on the role of α-synuclein in mediating post-ischemic brain damage.

Topics: alpha-Synuclein; Apoptosis; Brain Ischemia; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Bodies; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Protein Processing, Post-Translational; Ubiquitin-Protein Ligases

In 2017, it is two hundred years since James Parkinson provided the first complete clinical description of the disease named after him, fifty years since the introduction of high-dose D,L-DOPA treatment and twenty years since α-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson's disease and dementia with Lewy bodies as the third major synucleinopathy. Here we review our work, which led to the identification of α-synuclein in Lewy bodies, Lewy neurites and Papp-Lantos bodies, as well as what has happened since. Some of the experiments described were carried out in collaboration with ML Schmidt, JQ Trojanowski and VMY Lee.

Topics: alpha-Synuclein; History, 20th Century; History, 21st Century; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

Topics: alpha-Synuclein; Animals; Genetic Predisposition to Disease; History, 20th Century; History, 21st Century; Humans; Mutation; Parkinson Disease

The role of autophagy in cell survival and suppression of neurodegeneration was considered. We discussed its involvement in Alzheimer's, Parkinson's, and Huntington's diseases connected with accumulation of amy- loid-β, α-synuclein, and huntingtin, respectively. Autophagy is reduced in these diseases and in aging as well to various extent. Elimination of accumulated toxic proteins and structures is performed by autophagy mech- anisms (chaperon-mediated autophagy, macroautophagy, selected autophagy) in an interaction with ubiqui- tin-proteasome system. In many cases activation of mTOR-dependent autophagy and mTOR-independent regulatory pathways lead to the therapeutic effect of inhibition of neurodegeneration in cell cultures and an- imal models. Some autophagy enhancers such as resveratrol, metformin, rilmenidine, lithium, and curcumin are tested now in clinical trials.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Autophagy; Clinical Trials as Topic; Gene Expression Regulation; Humans; Huntingtin Protein; Huntington Disease; Metformin; Molecular Chaperones; Molecular Targeted Therapy; Neuroprotective Agents; Parkinson Disease; Proteasome Endopeptidase Complex; Sirolimus; TOR Serine-Threonine Kinases; Ubiquitin

Phosphorylated α-synuclein (phosαSYN) containing inclusions in neurons (Lewy bodies, LB) and nerve terminals (Lewy neurites, LN), the pathological hallmark of Parkinson's disease (PD), are not confined to the central nervous system, but have also been reported in peripheral tissues. However, the usefulness of αSYN/phosαSYN detection in tissues accessible to biopsies as a reliable biomarker for prodromal PD remains unclear. A systematic review of studies using biopsies of skin, olfactory and gastrointestinal (GI) tissues was conducted to evaluate the sensitivity and specificity of both αSYN and phosαSYN staining in PD patients. Data analysis was hampered by the diversity of the methods used, e.g. choice of biopsy sites, tissue processing, staining protocols and evaluation of the findings. Tissue obtained from GI tract/salivary glands (13 post-mortem, 13 in vivo studies) yielded the highest overall sensitivity and specificity compared to skin (three post-mortem, eight in vivo studies) and olfactory mucosa/bulb (six post-mortem studies, one in vivo study). In contrast to phosαSYN, αSYN was more consistently detectable in peripheral tissues of healthy controls. GI tract/salivary glands appear to be the most promising candidate tissue for peripheral biopsy-taking. phosαSYN is considered as the marker of choice to delineate pathological aggregates from normal αSYN regularly found in peripheral neural tissues. However, the sensitivity and specificity of phosαSYN are not yet acceptable for using phosαSYN as a reliable peripheral biomarker for PD in clinical routine. Further refinement regarding the interpretation of the peripheral αSYN/phosαSYN burden and the phenotypical definition of peripheral LB/LN is needed to optimize screening methods for prodromal PD.

Topics: alpha-Synuclein; Biomarkers; Gastrointestinal Tract; Humans; Parkinson Disease; Salivary Glands

Vaccination is increasingly being investigated as a potential treatment for synucleinopathies, a group of neurodegenerative diseases including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies associated with α-synuclein pathology. All lack a causal therapy. Development of novel, disease-altering treatment strategies is urgently needed. Vaccination has positioned itself as a prime strategy for addressing these diseases because it is broadly applicable, requires infrequent administration, and maintains low production costs for treating a large population or as a preventive measure. Current evidence points to a causal role of misfolded α-synuclein in the development and progression of synucleinopathies. In the past decade, significant progress in active immunization against α-synuclein has been shown both in preclinical animal models and in early clinical development. In this review, we describe the state-of-the-art in active immunization approaches to synucleinopathies, with a focus on advances in Parkinson's disease (PD) and multiple-system atrophy (MSA). We first review preclinical animal models, highlighting their progress in translation to the clinical setting. We then discuss current clinical applications, stressing different approaches taken to address α-synuclein pathology. Finally, we address challenges, trends, and future perspectives of current vaccination programs.

Topics: alpha-Synuclein; Animals; Humans; Multiple System Atrophy; Parkinson Disease; Vaccination

α-Synuclein (αSyn) is a highly abundant neuronal protein whose exact structure and function are under debate. Misfolding and aggregation of this normally soluble, 140-residue polypeptide underlies a group of neurodegenerative disorders called synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The αSyn field has focused increasing attention on the hypotheses that certain aggregates of αSyn may be directly toxic to the neurons in which they arise and/or that aggregates can be released from some neurons and diffuse by undefined mechanisms to other neurons to seed αSyn in the recipient cells, thus propagating neuropathology by a non-cell autonomous process ('pathogenic spread'). While intense interest in these hypotheses has led to new approaches and tools to model aspects of the disorders, it is important to analyze which molecular events initiate αSyn aggregation inside neurons in the first place. Here, we review new insights into how neuronal αSyn homeostasis may be maintained under physiological conditions but perturbed by pathological factors.

Topics: alpha-Synuclein; Brain; Cell Membrane; Homeostasis; Humans; Lewy Body Disease; Neurodegenerative Diseases; Neurons; Parkinson Disease; Protein Multimerization

Parkinson's disease is a progressive neurodegenerative disorder with multiple factors contributing to increasing severity of pathology in specific brain regions. The Braak hypothesis of Lewy pathology progression in Parkinson's disease proposes a systematic spread of α-synuclein that can be staged, with the later stages correlating with clinical aspects of the disease. The spread of pathology through the different stages suggests progression, a theory that has proven correct from evidence of pathology in healthy neurons grafted into the brains of patients with Parkinson's disease. Progression of pathology occurs on a number of levels, within a cell, between nearby cells, and then over longer distances throughout the brain, and evidence using prion proteins suggests two dissociable mechanisms-intracellular toxicity versus a nontoxic infectious mechanism for propagation. In Parkinson's disease, intracellular changes associated with mitochondria and lysosome dysfunction appear important for α-synuclein propagation, with high stress conditions favoring mitochondrial cell death mechanisms. Functional neurons appear necessary for propagation. Unconventional exocytosis releases α-synuclein under stress conditions, and endocytic uptake occurs in nearby cells. This cell-to-cell transmission of α-synuclein has been recapitulated in both cell culture and animal models, but the timeframe of transmission is considerably shorter than that observed in transplanted neurons. The time course of Lewy pathology formation in patients is consistent with the long time course observed in grafted neurons, and the restricted neuronal loss in Parkinson's disease is potentially important for the propagation of α-synuclein through relatively intact circuits.

Topics: alpha-Synuclein; Animals; Humans; Parkinson Disease

Currently there are no disease-modifying alternatives for the treatment of most neurodegenerative disorders. The available therapies for diseases such as Parkinson's disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), in which the protein alpha-synuclein (α-Syn) accumulates within neurons and glial cells with toxic consequences, are focused on managing the disease symptoms. However, using strategic drug combinations and/or multi-target drugs might increase the treatment efficiency when compared with monotherapies. Synucleinopathies are complex disorders that progress through several stages, and toxic α-Syn aggregates exhibit prion-like behavior spreading from cell to cell. Therefore, it follows that these neurodegenerative disorders might require equally complex therapeutic approaches to obtain significant and long-lasting results. Hypothetically, therapies aimed at reducing α-Syn accumulation and cell-to-cell transfer, such as immunotherapy against α-Syn, could be combined with agents that reduce neuroinflammation with potential synergistic outcomes. Here we review the current evidence supporting this type of approach, suggesting that such rational therapy combinations, together with the use of multi-target drugs, may hold promise as the next logical step for the treatment of synucleinopathies.

Topics: alpha-Synuclein; Animals; Combined Modality Therapy; Humans; Immunotherapy; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

Progressive aggregation of alpha-synuclein (αS) through formation of amorphous pale bodies to mature Lewy bodies or in neuronal processes as Lewy neurites may be the consequence of conformational protein changes and accumulations, which structurally represents "molecular template". Focal initiation and subsequent spread along anatomically connected structures embody "structural template". To investigate the hypothesis that both processes might be closely associated and involved in the progression of αS pathology, which can be observed in human brains, αS amyloidogenic precursors termed "seeds" were experimentally injected into the brain or peripheral nervous system of animals. Although these studies showed that αS amyloidogenic seeds can induce αS pathology, which can spread in the nervous system, the findings are still not unequivocal in demonstrating predominant transsynaptic or intraneuronal spreads either in anterograde or retrograde directions. Interpretation of some of these studies is further complicated by other concurrent aberrant processes including neuroimmune activation, injury responses and/or general perturbation of proteostasis. In human brain, αS deposition and neuronal degeneration are accentuated in distal axon/synapse. Hyperbranching of axons is an anatomical commonality of Lewy-prone systems, providing a structural basis for abundance in distal axons and synaptic terminals. This neuroanatomical feature also can contribute to such distal accentuation of vulnerability in neuronal demise and the formation of αS inclusion pathology. Although retrograde progression of αS aggregation in hyperbranching axons may be a consistent feature of Lewy pathology, the regional distribution and gradient of Lewy pathology are not necessarily compatible with a predictable pattern such as upward progression from lower brainstem to cerebral cortex. Furthermore, "focal Lewy body disease" with the specific isolated involvement of autonomic, olfactory or cardiac systems suggests that spread of αS pathology is not always consistent. In many instances, the regional variability of Lewy pathology in human brain cannot be explained by a unified hypothesis such as transsynaptic spread. Thus, the distribution of Lewy pathology in human brain may be better explained by variable combinations of independent focal Lewy pathology to generate "multifocal Lewy body disease" that could be coupled with selective but variable neuroanatomical spread of αS pathology. More flexib

Topics: alpha-Synuclein; Animals; Axons; Brain; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease

Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. In Alzheimer's disease, levels of increased CSF tau protein and decreased levels of β-amyloid 1-42 (Aβ42) have been shown to correlate with brain plaque formation and tangle pathology. Intracellular Lewy inclusions containing aggregated α-synuclein (α-syn) represent a pathological hallmark of Parkinson's disease (PD). In most - but not all - studies published to date total CSF α-syn concentrations have been found to be decreased in disorders related to α-syn pathology, that is, PD, dementia with Lewy bodies and multiple system atrophy. However, these reports show extensive signal overlap among tested individuals, thereby diminishing its potential for routine use in clinical practice. To investigate potential biological (i.e., non-technical) confounders of reported CSF levels for α-syn, Aβ42, and tau in PD and related disorders, we carried out a methodical review of known factors that underlie signal variability and speculate on those that have not yet been tested. We discuss several biological factors, such as neuropathology, demographics, clinical phenotype, progression and duration of disease, concomitant illnesses and, last but not least, pharmacotherapy, which in isolation or combination can substantially alter values for CSF proteins of interest. Enhanced implementation of standardized clinical protocols, streamlined operating procedures, and further progress in the development of validated assays for CSF proteins have the potential to (i) inform us as to the pathogenesis of disease, (ii) support the laboratory-based diagnosis for symptomatic subjects in the future, and (iii) facilitate breakthrough therapies to alter the course of neurodegenerative disorders, such as PD and Alzheimer's disease. Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. To investigate potential biological confounders of reported CSF levels for α-synuclein (α-Syn), amyloid-β 1-42(Aβ42) and tau protein in Parkinson's disease and related disorders, we reviewed the current literature for known factors that underlie signal variability and speculate on those that have not yet been tested. This article is part of a special issue on Parkinson disease.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Animals; Biomarkers; Cerebrospinal Fluid Proteins; Clinical Trials as Topic; Cognition Disorders; Humans; Parkinson Disease; Peptide Fragments; tau Proteins

Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer’s disease, α-synuclein in Alzheimer’s disease and Parkinson’s disease, and tau in Alzheimer’s disease and frontotemporal dementia.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Humans; Immunotherapy; Neurodegenerative Diseases; Parkinson Disease; tau Proteins

Alpha-Synuclein is found in the neuronal cells but its native function is not well known. While α -synuclein is an intrinsically disordered protein that adopts a helical conformation upon membrane binding, numerous studies have shown that oligomeric β-forms of this protein are cytotoxic. This response to misfolded species contributes to Parkinson's Disease etiology and symptoms. The resulting amyloid fibrils are an established diagnostic in Parkinson's Disease. In this review, we focus on strategies that have been used to inhibit the amyloidogenesis of α -synuclein either by stabilizing the native state, or by redirecting the pathway to less toxic aggregates. Small molecules such as polyphenols, peptides as well as large proteins have proven effective at protecting cells against the cytotoxicity of α-synuclein. These strategies may lead to the development of therapeutic agents that could prove useful in combating this disease.

Topics: alpha-Synuclein; Amyloid; Amyloidosis; Animals; Humans; Mutation; Parkinson Disease; Protein Folding

While immune control is associated with nigrostriatal neuroprotection for Parkinson's disease, direct cause and effect relationships have not yet been realized, and modulating the immune system for therapeutic gain has been openly debated. Here, we review how innate and adaptive immunity affect disease pathobiology, and how each could be harnessed for treatment. The overarching idea is to employ immunopharmacologics as neuroprotective strategies for disease. The aim of the current work is to review disease-modifying treatments that are currently being developed as neuroprotective strategies for PD in experimental animal models and for human disease translation. The long-term goal of this research is to effectively harness the immune system to slow or prevent PD pathobiology.

Topics: alpha-Synuclein; Animals; Humans; Immunomodulation; Neuroprotective Agents; Parkinson Disease; T-Lymphocytes, Regulatory

Pathologically, Parkinson's disease (PD) is characterized by nigral cell loss and Lewy pathology in the remaining neurons. Whereas the motor symptoms of PD show a marked response to dopamine replacement therapy, many of the non-motor symptoms are resistant to treatment. This suggests that in addition to nigral cell loss, widespread Lewy pathology in the nervous system is associated with the manifestations of PD. Areas covered: Although the mechanism of Lewy body formation remains largely unknown, it is becoming clear that changes in the behavior of α-synuclein are critical in this process. α-Synuclein behaves differently depending on the lipid composition of membranes with which it interacts; therefore, one can postulate that the altered lipid composition of neuronal membranes may lead to Lewy pathology. The lipid composition of cellular membranes is consistently altered in the brains of patients with PD, and Lewy pathology is a common feature of several human lipidoses with mutations in enzymes that affect membrane lipids. This further supports the concept that alterations in the membrane lipids of neurons are central to Lewy pathology. Expert opinion: This concept provides a new platform to establish models for the development of novel treatments for PD.

Topics: alpha-Synuclein; Animals; Brain; Dopamine; Humans; Lewy Bodies; Membrane Lipids; Molecular Targeted Therapy; Parkinson Disease; Substantia Nigra

Parkinson's disease (PD is a progressive neurological disorder characterized by the degeneration and death of midbrain dopamine and non-dopamine neurons in the brain leading to motor dysfunctions and other symptoms, which seriously influence the quality of life of PD patients. The drug L-dopa can alleviate the motor symptoms in PD, but so far there are no rational therapies targeting the underlying neurodegenerative processes. Despite intensive research, the molecular mechanisms causing neuronal loss are not fully understood which has hampered the development of new drugs and disease-modifying therapies. Neurotrophic factors are by virtue of their survival promoting activities attract candidates to counteract and possibly halt cell degeneration in PD. In particular, studies employing glial cell line-derived neurotrophic factor (GDNF) and its family member neurturin (NRTN), as well as the recently described cerebral dopamine neurotrophic factor (CDNF) and the mesencephalic astrocyte-derived neurotrophic factor (MANF) have shown positive results in protecting and repairing dopaminergic neurons in various models of PD. Other substances with trophic actions in dopaminergic neurons include neuropeptides and small compounds that target different pathways impaired in PD, such as increased cell stress, protein handling defects, dysfunctional mitochondria and neuroinflammation. In this review, we will highlight the recent developments in this field with a focus on trophic factors and substances having the potential to beneficially influence the viability and functions of dopaminergic neurons as shown in preclinical or in animal models of PD.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Glial Cell Line-Derived Neurotrophic Factor; Humans; Mitochondria; Nerve Growth Factors; Neuroprotective Agents; Neurturin; Parkinson Disease; Recombinant Proteins; Unfolded Protein Response

Parkinson's disease is a progressive neurological disorder that is characterized by the formation of intracellular protein inclusion bodies composed primarily of a misfolded and aggregated form of the protein α-synuclein. There is growing evidence that supports the prion-like hypothesis of α-synuclein progression. This hypothesis postulates that α-synuclein is a prion-like pathological agent and is responsible for the progression of Parkinson pathology in the brain. Potential misfolding or aggregation of α-synuclein that might occur in the peripheral nervous system as a result of some insult, environmental or genetic (or more likely a combination of both) that might spread into the midbrain, eventually causing degeneration of the neurons in the substantia nigra. As the disease progresses further, it is likely that α-synuclein pathology continues to spread throughout the brain, including the cortex, leading to deterioration of cognition and higher brain functions. While it is unknown why α-synuclein initially misfolds and aggregates, a great deal has been learned about how the cell handles aberrant α-synuclein assemblies. In this review, we focus on these mechanisms and discuss them in an attempt to define the role that they might play in the propagation of misfolded α-synuclein from cell-to-cell. The prion-like hypothesis of α-synuclein pathology suggests a method for the transmission of misfolded α-synuclein from one neuron to another. This hypothesis postulates that misfolded α-synuclein becomes aggregation prone and when released and taken up by neighboring cells, seeds further misfolding and aggregation. In this review we examine the cellular mechanisms that are involved in the processing of α-synuclein and how these may contribute to the prion-like propagation of α-synuclein pathology. This article is part of a special issue on Parkinson disease.

Topics: alpha-Synuclein; Animals; Humans; Parkinson Disease; Prion Diseases; Prion Proteins; Protein Aggregates; Protein Transport

Since diagnosis of Parkinson's disease (PD) is mostly based on clinical criteria, it is almost impossible to formulate an early diagnosis, as well as a timely differential diagnosis versus other parkinsonisms. A great effort in searching reliable biomarkers both for early diagnosis and prognosis in PD is currently ongoing. Cerebrospinal fluid has been widely investigated as potential source for such biomarkers, with particular emphasis on α-synuclein (α-syn) species. We reviewed all the clinical studies carried out so far on cerebrospinal fluid quantification of α-syn species in PD. Current evidence supports the value of total and oligomeric α-syn in PD diagnosis and in the differential diagnosis of PD and other parkinsonisms. Conversely, the role of α-syn species in PD prognosis remains unsatisfactory.

Topics: alpha-Synuclein; Biomarkers; Diagnosis, Differential; Humans; Parkinson Disease; Prognosis

The etiology and pathogenesis of Parkinson's disease (PD) is unknown, aging being the strongest risk factor for brain degeneration. Understanding PD pathogenesis and how aging increases the risk of disease would aid the development of therapies able to slow or prevent the progression of this neurodegenerative disorder. In this review we provide an overview of the most promising therapeutic targets and strategies to delay the loss of dopaminergic neurons observed both in PD and aging. Among them, handling alpha-synuclein toxicity, enhancing proteasome and lysosome clearance, ameliorating mitochondrial disruptions and modifying the glial environment are so far the most promising candidates. These new and conventional drugs may present problems related to their labile nature and to the difficulties in reaching the brain. Thus, we highlight the latest types of drug delivery system (DDS)-based strategies for PD treatment, including DDS for local and systemic drug delivery. Finally, the ongoing challenges for the discovery of new targets and the opportunities for DDS-based therapies to improve and efficacious PD therapy will be discussed.

Topics: Aging; alpha-Synuclein; Antioxidants; Brain; Dopamine; Dopamine Agonists; Drug Delivery Systems; Genetic Therapy; Humans; Lewy Bodies; Lysosomes; Mitochondria; Nerve Growth Factors; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Peptides; Proteasome Endopeptidase Complex

The development of α-synuclein immunoreactive aggregates in selectively vulnerable neuronal types of the human central, peripheral, and enteric nervous systems is crucial for the pathogenesis of sporadic Parkinson's disease. The presence of these lesions persists into the end phase of the disease, a process that is not subject to remission. The initial induction of α-synuclein misfolding and subsequent aggregation probably occurs in the olfactory bulb and/or the enteric nervous system. Each of these sites is exposed to potentially hostile environmental factors. Once formed, the aggregates appear to be capable of propagating trans-synaptically from nerve cell to nerve cell in a virtually self-promoting pathological process. A regional distribution pattern of aggregated α-synuclein emerges that entails the involvement of only a few types of susceptible and axonally interconnected projection neurons within the human nervous system. One major route of disease progression may originate in the enteric nervous system and retrogradely reach the dorsal motor nucleus of the vagal nerve in the lower brainstem. From there, the disease process proceeds chiefly in a caudo-rostral direction through visceromotor and somatomotor brainstem centres to the midbrain, forebrain, and cerebral cortex. Spinal cord centres may become involved by means of descending projections from involved lower brainstem nuclei as well as by sympathetic projections connecting the enteric nervous system with postganglionic peripheral ganglia and preganglionic nuclei of the spinal cord. The development of experimental cellular and animal models is helping to explain the mechanisms of how abnormal α-synuclein can undergo aggregation and how transmission along axonal connectivities can occur, thereby encouraging the initiation of potential disease-modifying therapeutic strategies for sporadic Parkinson's disease.

Topics: alpha-Synuclein; Animals; Disease Progression; Enteric Nervous System; Humans; Parkinson Disease

One of the key molecular events underlying the pathogenesis of Parkinson's disease (PD) is the aberrant misfolding and aggregation of the α-synuclein (αS) protein into higher-order oligomers that play a key role in neuronal dysfunction and degeneration. A wealth of experimental data supports the hypothesis that the neurotoxicity of αS oligomers is intrinsically linked with their ability to interact with, and disrupt, biological membranes; especially those membranes having negatively-charged surfaces and/or lipid packing defects. Consequences of αS-lipid interaction include increased membrane tension, permeation by pore formation, membrane lysis and/or leakage due to the extraction of lipids from the bilayer. Moreover, we assert that the interaction of αS with a liquid-disordering phospholipid uniquely enriched in mitochondrial membranes, namely cardiolipin (1,3-diphosphatidyl-sn-glycerol, CL), helps target the αS oligomeric complexes intracellularly to mitochondria. Binding mediated by CL may thus represent an important pathomechanism by which cytosolic αS could physically associate with mitochondrial membranes and disrupt their integrity. Impaired mitochondrial function culminates in a cellular bioenergetic crisis and apoptotic death. To conclude, we advocate the accelerated discovery of new drugs targeting this pathway in order to restore mitochondrial function in PD.

Topics: alpha-Synuclein; Animals; Cardiolipins; Cell Membrane; Humans; Mitochondrial Dynamics; Mitochondrial Membranes; Parkinson Disease

Immunotherapy using antibodies targeting alpha-synuclein has proven to be an effective strategy for ameliorating pathological and behavioral deficits induced by excess pathogenic alpha-synuclein in various animal and/or cellular models. However, the process of selecting the anti-alpha-synuclein antibody with the best potential to treat synucleinopathies in humans is not trivial. Critical to this process is a better understanding of the pathological processes involved in the synucleinopathies and how antibodies are able to influence these. We will give an overview of the first proof-of-concept studies in rodent disease models and discuss challenges associated with developing antibodies against alpha-synuclein resulting from the distribution and structural characteristics of the protein. We will also provide a status on the passive immunization approaches targeting alpha-synuclein that have entered, or are expected to enter, clinical evaluation.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Immunization, Passive; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

The lack of effective therapies for neurodegenerative disorders is one of the most relevant challenges of this century, considering that, as the global population ages, the incidence of these type of diseases is quickly on the rise. Among these disorders, synucleinopathies, which are characterized by the abnormal accumulation and spreading of the synaptic protein alpha-synuclein in the brain, already constitute the second leading cause of parkinsonism and dementia in the elderly population. Disorders with alpha-synuclein accumulation include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Numerous therapeutic alternatives for synucleinopathies are being tested in pre-clinical models and in the clinic; however, only palliative treatments addressing the dopaminergic deficits are approved to date, and no disease-modifying options are available yet. In this article, we provide a brief overview of therapeutic approaches currently being explored for synucleinopathies, and suggest possible explanations to the clinical trials outcomes. Finally, we propose that a deeper understanding of the pathophysiology of synucleinopathies, together with a combination of therapies tailored to each disease stage, may lead to better therapeutic outcomes in synucleinopathy patients. Synucleinopathies, neurodegenerative disorders characterized by the abnormal accumulation of the protein alpha-synuclein, constitute the second leading cause of parkinsonism and dementia in the elderly population, however, no disease-modifying options are available yet. In this review, we summarize the therapeutic approaches currently being explored for synucleinopathies, suggest possible explanations to the clinical outcomes, and propose areas of further therapeutic improvement. This article is part of a special issue on Parkinson disease.

Topics: alpha-Synuclein; Animals; Clinical Trials as Topic; Dementia; Genetic Therapy; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Stem Cell Transplantation

It has been recognized for many years that a number of chronic neurodegenerative diseases of the CNS are characterized by the development of intracellular inclusion bodies, but it is only relatively recently that the core proteins defining these pathologies have been defined. One such protein is alpha synuclein, that was found to be the main component of Lewy bodies in the late 1990s, and this discovery reinforced the emerging view that alpha synuclein was intimately linked to diseases characterized by this type of pathology--namely Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Furthermore at around this time, this same protein was also found within the glial inclusion bodies of patients dying with multiple system atrophy (MSA). These three disorders constitute the majority of patients with an 'alpha synucleinopathy', although there are a number of rarer conditions that can also cause this pathology including inherited metabolic disorders such as Gaucher's disease (GD). In this review, we will concentrate on PD, the commonest alpha synucleinopathy, and its associated dementia (PDD), as well as discussing DLB and MSA and will highlight how the clinical features of these conditions vary as a function of pathology.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

Topics: alpha-Synuclein; Animals; Biomarkers; Brain; Humans; Parkinson Disease; Prodromal Symptoms

Although the physiological function of α-synuclein is not fully understood, it has been suggested to primarily localize to the presynaptic terminals of mature neurons, where it fulfills roles in synaptic function and plasticity. Based on current knowledge, α-synuclein (αSYN) is thought to be involved in maintaining neurotransmitter homeostasis by regulating synaptic vesicle fusion, clustering, and trafficking between the reserve and ready-releasable pools, as well as interacting with neurotransmitter membrane transporters. In this review, we focus on evidence proposing synapses as the main site of αSYN pathology and its propagation in Parkinson's disease and dementia with Lewy bodies, which belong to a group of neurodegenerative diseases known as α-synucleinopathies. We provide an overview of the evidence supporting presynaptic dysfunction as the primary event in the pathogenesis of these conditions.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Parkinson Disease; Synapses

In recent years, several studies have investigated the potential of immunohistochemical detection of α-synuclein in the gastrointestinal tract to diagnose Parkinson's disease (PD). Although methodological heterogeneity has hindered comparability between studies, it has become increasingly apparent that the high sensitivity and specificity reported in preliminary studies has not been sustained in subsequent large-scale studies. What constitutes pathological α-synuclein in the alimentary canal that could distinguish between PD patients and controls and how this can be reliably detected represent key outstanding questions in the field. In this review, we will comment on and compare the variable technical aspects from previous studies, and by highlighting some advantages and shortcomings we hope to delineate a standardized approach to facilitate the consensus criteria urgently needed in the field. Furthermore, we will describe alternative detection techniques to conventional immunohistochemistry that have recently emerged and may facilitate ease of interpretation and reliability of gastrointestinal α-synuclein detection. Such techniques have the potential to detect the presence of pathological α-synuclein and include the paraffin-embedded tissue blot, the proximity ligation assay, the protein misfolding cyclic amplification technique, and the real-time quaking-induced conversion assay. Finally, we will review 2 nonsynonymous theories that have driven enteric α-synuclein research, namely, (1) that α-synuclein propagates in a prion-like fashion from the peripheral nervous system to the brain via vagal connections and (2) that gastrointestinal α-synuclein deposition may be used as a clinically useful biomarker in PD.

Topics: alpha-Synuclein; Biomarkers; Gastrointestinal Tract; Humans; Parkinson Disease

Evidence from human postmortem material, transgenic mice, and cellular/animal models of PD link alpha-synuclein accumulation to alterations in the autophagy lysosomal pathway. Conversely, alpha-synuclein mutations related to PD pathogenesis, as well as post-translational modifications of the wild-type protein, result in the generation of aberrant species that may impair further the function of the autophagy lysosomal pathway, thus generating a vicious cycle leading to neuronal death. Moreover, PD-linked mutations in lysosomal-related genes, such as glucocerebrosidase, have been also shown to contribute to alpha-synuclein accumulation and related toxicity, indicating that lysosomal dysfunction may, in part, account for the neurodegeneration observed in synucleinopathies. In the current review, we summarize findings related to the inter-relationship between alpha-synuclein and lysosomal proteolytic pathways, focusing especially on recent experimental strategies based on the manipulation of the autophagy lysosomal pathway to counteract alpha-synuclein-mediated neurotoxicity in vivo. Pinpointing the factors that regulate alpha-synuclein association to the lysosome may represent potential targets for therapeutic interventions in PD and related synucleinopathies.

Topics: alpha-Synuclein; Animals; Autophagy; Glucosylceramidase; Humans; Lysosomes; Parkinson Disease

The diagnosis of Parkinson's disease (PD) currently relies on the appearance of certain clinical features. However, these features appear only years after the loss of nigral dopaminergic neurons. The progression of PD may be measured using clinical rating scales that are subjective and that have a variable inter-rater consistency. There is a growing need for a biomarker that will allow for early detection of the disease as well as provide a measure of disease progression. In this article, we review different biomarkers, with a focus on functional imaging techniques, which while imperfect, currently provide the best approach to this problem. We also discuss the use of structural imaging and emerging progress in other biochemical and molecular markers. While there is no single biomarker that will satisfy all requirements, a combination is likely to be of great use in identifying those subjects most likely to benefit from neuroprotective therapies, as well as in monitoring the effects of any interventions.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Biomarkers; Brain; Diffusion Tensor Imaging; Disease Progression; Dopaminergic Neurons; Functional Neuroimaging; Humans; Inflammation; Intracellular Signaling Peptides and Proteins; Magnetic Resonance Imaging; Mutation; Neuroimaging; Oncogene Proteins; Oxidative Stress; Parkinson Disease; Peptide Fragments; Positron-Emission Tomography; Protein Deglycase DJ-1; Substantia Nigra; tau Proteins; Tomography, Emission-Computed, Single-Photon

The aggregation of alpha synuclein (α-syn) is a neuropathological feature that defines a spectrum of disorders collectively termed synucleinopathies, and of these, Parkinson's disease (PD) is arguably the best characterized. Aggregated α-syn is the primary component of Lewy bodies, the defining pathological feature of PD, while mutations or multiplications in the α-syn gene result in familial PD. The high correlation between α-syn burden and PD has led to the hypothesis that α-syn aggregation produces toxicity through a gain-of-function mechanism. However, α-syn has been implicated to function in a diverse range of essential cellular processes such as the regulation of neurotransmission and response to cellular stress. As such, an alternative hypothesis with equal explanatory power is that the aggregation of α-syn results in toxicity because of a toxic loss of necessary α-syn function, following sequestration of functional forms α-syn into insoluble protein aggregates. Within this review, we will provide an overview of the literature linking α-syn to PD and the knowledge gained from current α-syn-based animal models of PD. We will then interpret these data from the viewpoint of the α-syn loss-of-function hypothesis and provide a potential mechanistic model by which loss of α-syn function could result in at least some of the neurodegeneration observed in PD. By providing an alternative perspective on the etiopathogenesis of PD and synucleinopathies, this may reveal alternative avenues of research in order to identify potential novel therapeutic targets for disease modifying strategies. The correlation between α-synuclein burden and Parkinson's disease pathology has led to the hypothesis that α-synuclein aggregation produces toxicity through a gain-of-function mechanism. However, in this review, we discuss data supporting the alternative hypothesis that the aggregation of α-synuclein results in toxicity because of loss of necessary α-synuclein function at the presynaptic terminal, following sequestration of functional forms of α-synuclein into aggregates.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Humans; Neurons; Parkinson Disease

The role of mutations in the gene GBA1 encoding the lysosomal hydrolase β-glucocerebrosidase for the development of synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, was only very recently uncovered. The knowledge obtained from the study of carriers or patients suffering from Gaucher disease (a common lysosomal storage disorder because of GBA1 mutations) is of particular importance for understanding the role of the enzyme and its catabolic pathway in the development of synucleinopathies. Decreased activity of β-glucocerebrosidase leads to lysosomal dysfunction and the accumulation of its substrate glucosylceramide and related lipid derivatives. Glucosylceramide is suggested to stabilize toxic oligomeric forms of α-synuclein that negatively influence the activity of β-glucocerebrosidase and to partially block export of newly synthesized β-glucocerebrosidase from the endoplasmic reticulum to late endocytic compartments, amplifying the pathological effects of α-synuclein and ultimately resulting in neuronal cell death. This pathogenic molecular feedback loop and most likely other factors (such as impaired endoplasmic reticulum-associated degradation, activation of the unfolded protein response and dysregulation of calcium homeostasis induced by misfolded GC mutants) are involved in shifting the cellular homeostasis from monomeric α-synuclein towards oligomeric neurotoxic and aggregated forms, which contribute to Parkinson's disease progression. From a therapeutic point of view, strategies aiming to increase either the expression, stability or delivery of the β-glucocerebrosidase to lysosomes are likely to decrease the α-synuclein burden and may be useful for an in depth evaluation at the organismal level. Lysosomes are critical for protein and lipid homeostasis. Recent research revealed that dysfunction of this organelle contributes to the development of neurodegenerative diseases such as Parkinson's disease (PD). Mutations in the lysosomal hydrolase β-glucocerebrosidase (GBA1) are a major risk factor for the development of PD and the molecular events linked to the reduced activity of GBA1 and the pathological accumulation of lipids and α-synuclein are just at the beginning to be understood. New therapeutic concepts in regards to how to increase the expression, stability, or delivery of β-glucocerebrosidase to lysosomes are currently developed. This article is part of a special issue on Parkinson disease.

Topics: alpha-Synuclein; Animals; Enzyme Activation; Glucosylceramidase; Humans; Lysosomes; Metabolic Clearance Rate; Parkinson Disease

Growing evidence indicates that small extracellular vesicles, called exosomes, are prominent mediators of neurodegenerative diseases such as prion, Alzheimer's and Parkinson's disease. Exosomes contain neurodegenerative disease associated proteins such as the prion protein, β-amyloid and α-synuclein. Only demonstrated so far in vivo with prion disease, exosomes are hypothesised to also facilitate the spread of β-amyloid and α-synuclein from their cells of origin to the extracellular environment. In the current review, we will discuss the role of exosomes in Alzheimer's and Parkinson's disease including their possible contribution to disease propagation and pathology and highlight their utility as a diagnostic in neurodegenerative disease.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Biomarkers; Exosomes; Extracellular Vesicles; Humans; Parkinson Disease; Protein Folding; Protein Transport

In this review the structural and functional imaging changes associated with the synucleinopathies PD, MSA, and dementias associated with Lewy bodies are reviewed. The role of imaging for supporting differential diagnosis, detecting subclinical disease, and following disease progression is discussed and its potential use for monitoring disease progression is debated. © 2016 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Substantia Nigra

Topics: Aged; alpha-Synuclein; Cataract; Cataract Extraction; Crystallins; Female; Humans; Lens, Crystalline; Male; Parkinson Disease

Mutations in the F-box only protein 7 (FBXO7) gene, located on chromosome 22q12-q13, have recently been identified as having distinct clinical features in patients with hereditary Parkinson's disease (PD). Pathologically, α-synuclein-positive inclusions have been identified using anti-FBXO7 antibody staining techniques. In the present study, we screened entire exons of FBXO7 from 271 patients (231 PD and 40 multiple system atrophy [MSA]), of which 221 samples were of Japanese origin. The PD patients (n = 231) comprised 31 autosomal dominant, 82 autosomal recessive, and 118 sporadic forms. The 40 cases of MSA consisted of 8 autosomal dominant, 2 autosomal recessive, and 30 sporadic forms. We detected a Turkish patient with autosomal recessive inheritance, harboring a homozygous truncating mutation, Arg498Stop (p.R498X), in the FBXO7 gene. Consequently, we evaluated her and assessed the correlation between her clinical manifestations and genotypic analysis, although the FBXO7 p.R498X gene has lower frequency than others. Her age at onset was 17 years, and she clinically manifested with progressive parkinsonism and cognitive decline. In contrast, no pathogenic mutations in FBXO7 among PD and MSA patients of Japanese or other ethnicities were observed. Based on recent literature, we reviewed and compared the clinical findings and population differences between documented FBXO7 cases.

Topics: Adolescent; Adult; Aged; alpha-Synuclein; Chromosomes, Human, Pair 22; F-Box Proteins; Female; Genes, Dominant; Genes, Recessive; Genetic Association Studies; Humans; Japan; Male; Middle Aged; Multiple System Atrophy; Mutation; Parkinson Disease; Turkey; Young Adult

Lysosomal impairment is increasingly recognized as a central event in the pathophysiology of PD. Genetic associations between lysosomal storage disorders, including Gaucher disease and PD, highlight common risk factors and pathological mechanisms. Because the autophagy-lysosomal system is involved in the intralysosomal hydrolysis of dysfunctional proteins, lysosomal impairment may contribute to α-synuclein aggregation in PD. The degradation of α-synuclein is a complex process involving different proteolytic mechanisms depending on protein burden, folding, posttranslational modifications, and yet unknown factors. In this review, evidence for lysosomal dysfunction in PD and its intimate relationship with α-synuclein aggregation are discussed, after which the question of whether lysosomal proteins may serve as diagnostic biomarkers for PD is addressed. Changes in lysosomal enzymes, such as reduced glucocerebrosidase and cathepsin levels, have been observed in affected brain regions in PD patients. The detection of lysosomal proteins in CSF may provide a read-out of lysosomal dysfunction in PD and holds promise for the development of diagnostic PD biomarkers. Initial PD biomarker studies demonstrated altered lysosomal enzyme activities in CSF of PD patients when compared with controls. However, CSF lysosomal enzyme activities alone could not discriminate between PD patients and controls. The combination of CSF lysosomal markers with α-synuclein species and indicators of mitochondrial dysfunction, inflammation, and other pathological proteins in PD may be able to facilitate a more accurate diagnosis of PD. Further CSF biomarker studies are needed to investigate the utility of CSF lysosomal proteins as measures of disease state and disease progression in PD. © 2016 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Biomarkers; Humans; Lysosomal Storage Diseases; Parkinson Disease; Proteins

Several decades ago, a mysterious transmissible agent was found responsible for a group of progressive and lethal encephalopathies affecting the nervous system of both animals and humans. This infectious agent showed a strain-encoded manner of inheritance even though it lacked nucleic acids. The identification of infectious proteins resolved this apparent conundrum. Misfolded infectious protein particles, or prions, were found to exist as conformational isomers with a unique fingerprint that can be faithfully passaged to next generations. Protein-based strain-encoded inheritance is characterized by strain-specific infectivity and symptomatology. It is found in diverse organisms, such as yeast, fungi, and mammals. Now, this concept is revisited to examine the pathological role of amyloid proteins involved in neurodegenerative diseases where it might underlie certain types of dementia and motor-related neurodegenerative disorders. Given the discovery of the SNCA gene and the identification of its gene product, ɑ-synuclein (ɑ-SYN), as the main histopathological component of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, the scientific community was left puzzled by the fact that a single protein appeared to be involved in different diseases with diverging clinical phenotypes. Recent studies are now indicating that ɑ-SYN may act in a way similar to prions and that ɑ-SYN misfolded structural variants may behave as strains with distinct biochemical and functional properties inducing specific phenotypic traits, which might finally provide an explanation for the clinical heterogeneity observed between Parkinson's disease, MSA, and dementia with Lewy bodies patients. These crucial new findings may pave the way for unexplored therapeutic avenues and identification of new potential biomarkers. Parkinson's disease and other synucleinopathies share ɑ-synuclein deposits as a common histopathological hallmark. New and ongoing developments are now showing that variations in the aggregation process and the formation of ɑ-synuclein strains may be paralleled by the development of distinct synucleinopathies. Here, we review the recent developments and the role of strains in synucleinopathies. This article is part of a special issue on Parkinson disease.

Topics: alpha-Synuclein; Animals; Dementia; Genetic Variation; Humans; Lewy Body Disease; Multiple System Atrophy; Neurodegenerative Diseases; Parkinson Disease

The discovery of the central role of α-synuclein (αSyn) in the pathogenesis of Parkinson's disease (PD) has powered, in the last decade, the emergence of novel relevant models of this condition based on viral vector-mediated expression of the disease-causing protein or inoculation of toxic species of αSyn. Although the development of these powerful tools and models has provided considerable insights into the mechanisms underlying neurodegeneration in PD, it has also been translated into the expansion of the landscape of preclinical therapeutic strategies. Much attention is now brought to the proteotoxic mechanisms induced by αSyn and how to block them using strategies inspired by intrinsic cellular pathways such as the enhancement of cellular clearance by the lysosomal-autophagic system, through proteasome-mediated degradation or through immunization. The important effort undertaken by several laboratories and consortia to tackle these issues and identify novel targets warrants great promise for the discovery not only of neuroprotective approaches but also of restorative strategies for PD and other synucleinopathies. In this viewpoint, we summarize the latest advances in this new area of PD research and will discuss promising approaches and ongoing challenges. © 2016 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Animals; Humans; Parkinson Disease

Parkinson's disease (PD) is a common neurodegenerative disorder, characterized pathologically by the presence of α-synuclein (α-syn)-rich Lewy bodies. As clinical diagnosis of PD is challenging, misdiagnosis is common, highlighting the need for disease-specific and early stage biomarkers. Both early diagnosis of PD and adequate tracking of disease progression could significantly improve outcomes for patients, particularly in regard to existing and future disease modifying treatments. Given its critical roles in PD pathogenesis, α-syn may be useful as a biomarker of PD. The aim of this review is, therefore, to summarize the efficacy of tissue and body fluid α-syn measurements in the detection of PD as well as monitoring disease progression. In comparison to solid tissue specimens and biopsies, biofluid α-syn levels may be the most promising candidates in PD diagnosis and progression based on specificity, sensitivity and availability. Although α-syn has been tested most extensively in cerebrospinal fluid (CSF), the relatively invasive procedure for collecting CSF is not suitable in most clinical settings, leading to investigation of plasma, blood and saliva as alternatives. The exploration of combined biomarkers, along with α-syn, to improve diagnostic accuracy is also likely required.

Topics: alpha-Synuclein; Biomarkers; Humans; Parkinson Disease

Glycation is a spontaneous age-dependent posttranslational modification that can impact the structure and function of several proteins. Interestingly, glycation can be detected at the periphery of Lewy bodies in the brain in Parkinson's disease. Moreover, α-synuclein can be glycated, at least under experimental conditions. In Alzheimer's disease, glycation of amyloid β peptide exacerbates its toxicity and contributes to neurodegeneration. Recent studies establish diabetes mellitus as a risk factor for several neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. However, the mechanisms underlying this connection remain unclear. We hypothesize that hyperglycemia might play an important role in the development of these disorders, possibly by also inducing protein glycation and thereby dysfunction, aggregation, and deposition. Here, we explore protein glycation as a common player in Parkinson's and Alzheimer's diseases and propose it may constitute a novel target for the development of strategies for neuroprotective therapeutic interventions. © 2016 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Parkinson Disease

Topics: alpha-Synuclein; Humans; Immunity, Innate; Parkinson Disease

Synucleinopathies are a group of neurodegenerative diseases that share a common pathological lesion of intracellular protein inclusions largely composed by aggregates of alpha-synuclein protein. Accumulating evidence, including genome wide association studies, has implicated alpha-synuclein (SNCA) gene in the etiology of synucleinopathies. However, the precise variants within SNCA gene that contribute to the sporadic forms of Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and other synucleinopathies and their molecular mechanisms of action remain elusive. It has been suggested that SNCA expression levels are critical for the development of these diseases. Here, we review several model systems that have been developed to advance the understanding of the role of SNCA expression levels in the etiology of synucleinopathies. We also describe different molecular mechanisms that regulate SNCA gene expression and discuss possible strategies for SNCA down-regulation as means for therapeutic approaches. Finally, we highlight some examples that underscore the relationships between the genetic association findings and the regulatory mechanisms of SNCA expression, which suggest that genetic variability in SNCA locus is directly responsible, at least in part, to the changes in gene expression and explain the reported associations of SNCA with synucleinopathies. Future studies utilizing induced pluripotent stem cells (iPSCs)-derived neuronal lines and genome editing by CRISPR/Cas9, will allow us to validate, characterize, and manipulate the effects of particular cis-genetic variants on SNCA expression. Moreover, this model system will enable us to compare different neuronal and glial lineages involved in synucleinopathies representing an attractive strategy to elucidate-common and specific-SNCA-genetic variants, regulatory mechanisms, and vulnerable expression levels underlying synucleinopathy spectrum disorders. This forthcoming knowledge will support the development of precision medicine for synucleinopathies.

Topics: alpha-Synuclein; Animals; Epigenesis, Genetic; Gene Expression; Gene Expression Regulation; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Protein Aggregation, Pathological; Up-Regulation

Copper is a biometal essential for normal brain development and function, thus copper deficiency or excess results in central nervous system disease. Well-characterized disorders of disrupted copper homoeostasis with neuronal degeneration include Menkes disease and Wilson's disease but a large body of evidence also implicates disrupted copper pathways in other neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease and prion diseases. In this short review we critically evaluate the data regarding changes in systemic and brain copper levels in Parkinson's disease, where alterations in brain copper are associated with regional neuronal cell death and disease pathology. We review copper regulating mechanisms in the human brain and the effects of dysfunction within these systems. We then examine the evidence for a role for copper in pathogenic processes in Parkinson's disease and consider reports of diverse copper-modulating strategies in in vitro and in vivo models of this disorder. Copper-modulating therapies are currently advancing through clinical trials for Alzheimer's and Huntington's disease and may also hold promise as disease modifying agents in Parkinson's disease.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Brain; Copper; Homeostasis; Humans; Oxidative Stress; Parkinson Disease

Parkinson's disease (PD) and related synucleinopathies are characterized by extensive neuronal cell loss, which is potentially triggered by α-synuclein misfolding and aggregation. Therefore it is reasonable to suggest that treatments targeting α-synuclein could reduce its levels and toxicity, rescue neuronal cells and halt the neurodegeneration process. Several approaches to decrease α-synuclein levels were employed thus far, mainly by using β-synuclein, another protein from the same family, or immunotherapies. These treatments demonstrated some positive results in preclinical studies, which may pave the road to the development of new promising disease-modifying therapies (DMTs). This approach should be further examined in preclinical and clinical settings, together with a clear process in order to advance candidates, enable the ability to define when there are target engagements and to detect what is a meaningful pharmacological response, and how it will be translated in clinical efficacy.

Topics: alpha-Synuclein; beta-Synuclein; Humans; Parkinson Disease

Fibrillar inclusions of intraneuronal α-synuclein can be detected in certain brain areas from patients with Parkinson's disease (PD) and other disorders with Lewy body pathology. These insoluble protein aggregates do not themselves appear to have a prominent neurotoxic effect, whereas various α-synuclein oligomers appear harmful. Although it is incompletely known how the prefibrillar species may be pathogenic, they have been detected both within and on the outside of exosomes and other extracellular vesicles (EVs), suggesting that such structures may mediate toxic α-synuclein propagation between neurons. Vesicular transfer of α-synuclein may thereby contribute to the hierarchical spreading of pathology seen in the PD brain. Although the regulation of α-synuclein release via EVs is not understood, data suggest that it may involve other PD-related molecules, such as LRRK2 and ATP13A2. Moreover, new evidence indicates that CNS-derived EVs in plasma have the potential to serve as biomarkers for diagnostic purposes. In a recent study, levels of α-synuclein were found to be increased in L1CAM-positive vesicles isolated from plasma of PD patients compared to healthy controls, and follow-up studies will reveal whether α-synuclein in EVs could be developed as a future disease biomarker. Preferentially, toxic prefibrillar α-synuclein oligomers should then be targeted as a biomarker-as evidence suggests that they reflect the disease process more closely than total α-synuclein content. In such studies, it will be essential to adopt stringent EV isolation protocols in order to avoid contamination from the abundant pool of free plasma α-synuclein in different aggregational states.

Topics: alpha-Synuclein; Animals; Central Nervous System; Extracellular Vesicles; Humans; Nerve Degeneration; Parkinson Disease; Protein Multimerization

Abnormal accumulation of proteinaceous intraneuronal inclusions called Lewy bodies (LBs) is the neurpathological hallmark of Parkinson's disease (PD) and related synucleinopathies. These inclusions are mainly constituted of a presynaptic protein, α-synuclein (α-syn). Over the past decade, growing amounts of studies reported an aberrant accumulation of phosphorylated α-syn at the residue S129 (pS129) in the brain of patients suffering from PD, as well as in transgenic animal models of synucleinopathies. Whereas only a small fraction of α-syn (<4%) is phosphorylated in healthy brains, a dramatic accumulation of pS129 (>90%) has been observed within LBs, suggesting that this post-translational modification may play an important role in the regulation of α-syn aggregation, LBs formation and neuronal degeneration. However, whether phosphorylation at S129 suppresses or enhances α-syn aggregation and toxicity in vivo remains a subject of active debate. The answer to this question has important implications for understanding the role of phosphorylation in the pathogenesis of synucleinopathies and determining if targeting kinases or phosphatases could be a viable therapeutic strategy for the treatment of these devastating neurological disorders. In the present review, we explore recent findings from in vitro, cell-based assays and in vivo studies describing the potential implications of pS129 in the regulation of α-syn physiological functions, as well as its implication in synucleinopathies pathogenesis and diagnosis.

Topics: alpha-Synuclein; Animals; Brain; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Phosphorylation

Animal models of Parkinson's disease (PD) are important for understanding the mechanisms of the disease and can contribute to developing and validating novel therapeutics. Ideally, these models should replicate the cardinal features of PD, such as progressive neurodegeneration of catecholaminergic neurons and motor defects. Many current PD models emphasize pathological forms of α-synuclein, based on findings that autosomal dominant mutations in α-synuclein and duplications/triplications of the SNCA gene cause PD. In addition, Lewy bodies and Lewy neurites, primarily composed of α-synuclein, represent the predominant pathological characteristics of PD. These inclusions have defined features, such as insolubility in non-ionic detergent, hyperphosphorylation, proteinase K sensitivity, a filamentous appearance by electron microscopy, and β-sheet structure. Furthermore, it has become clear that Lewy bodies and Lewy neurites are found throughout the peripheral and central nervous system, and could account not only for motor symptoms, but also for non-motor symptoms of the disease. The goal of this review is to describe two new α-synuclein-based models: the recombinant adeno-associated viral vector-α-synuclein model and the α-synuclein fibril model. An advantage of both models is that they do not require extensive crossbreeding of rodents transgenic for α-synuclein with other rodents transgenic for genes of interest to study the impact of such genes on PD-related pathology and phenotypes. In addition, abnormal α-synuclein can be expressed in brain regions relevant for disease. Here, we discuss the features of each model, how each model has contributed thus far to our understanding of PD, and the advantages and potential caveats of each model. This review describes two α-synuclein-based rodent models of Parkinson's disease: the rAAV-α-synuclein model and the α-synuclein fibril model. The key features of these models are described, and the extent to which they recapitulate features of PD, such as α-synuclein inclusion formation, loss of dopaminergic synapses in the striatum, motor defects, inflammation, and dopamine neuron death. This article is part of a special issue on Parkinson disease.

Topics: alpha-Synuclein; Amyloid; Animals; Comprehension; Dependovirus; Disease Models, Animal; Genetic Vectors; Humans; Parkinson Disease; Recombinant Proteins

The term oligomeropathies defines the neurodegenerative disorders associated with protein misfolding, where small soluble aggregates (oligomers 4-200 KDa) are the cause of neuronal dysfunction and are responsible for spreading the pathology. The ability of these soluble β-sheet conformers to induce neuronal damage has been investigated in direct challenge with the monomeric and fibrillary structures, showing that only the oligomeric species affected the neurons. β amyloid oligomers were initially purified from Alzheimer brains and obtained using synthetic peptides. Together with the neuronal death, synaptic dysfunction, loss of spines, and LTP impairment were seen with the direct application of β amyloid oligomers. Similar results have been described with proteins associated with other neurodegenerative disorders. The biological activities of oligomeric forms of α synuclein have been described in Parkinson's disease and Lewy body dementia. Detrimental effects have been associated with the oligomeric forms of prion, tau, and huntingtin, the key proteins in prion diseases, frontotemporal dementia, and Huntington's disease, respectively. The molecular mechanisms of the oligomer-related toxic effects can be summarized under three headings: nonspecific perturbance of cellular and intracellular membranes, specific interaction with various cellular entities, and amyloid pore channel formation. To characterize and distinguish oligomer actions better, we compared the ability of β amyloid and α synuclein oligomers to induce cognitive impairment when applied directly into the brain in the same acute mouse model. We also investigated the role of inflammatory components. © 2016 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Humans; Parkinson Disease; Proteostasis Deficiencies

Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a special issue on Parkinson disease.

Topics: alpha-Synuclein; Animals; Genome-Wide Association Study; Humans; Mutation; Parkinson Disease; Ubiquitin-Protein Ligases

Developing new therapeutic strategies for Parkinson's disease requires cellular models. Current models reproduce the two most salient changes found in the brains of patients with Parkinson's disease: The degeneration of dopaminergic neurons and the existence of protein aggregates consisting mainly of α-synuclein. Cultured cells offer many advantages over studying Parkinson's disease directly in patients or in animal models. At the same time, the choice of a specific cellular model entails the requirement to focus on one aspect of the disease while ignoring others. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types the aspects of Parkinson's disease they model along with technical advantages and disadvantages. It might also be helpful for researchers from other fields consulting literature on cellular models of Parkinson's disease. Important models for the study of dopaminergic neuron degeneration include Lund human mesencephalic cells and primary neurons, and a case is made for the use of non-dopaminergic cells to model pathogenesis of non-motor symptoms of Parkinson's disease. With regard to α-synuclein aggregates, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. Cellular models reproduce the two most salient changes of Parkinson's disease, the degeneration of dopaminergic neurons and the existence of α-synuclein aggregates. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types and treatments the aspects of Parkinson's disease they model along with technical advantages and disadvantages. Furthermore, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. This article is part of a special issue on Parkinson disease.

Topics: alpha-Synuclein; Animals; Cell Line, Tumor; Cells, Cultured; Disease Models, Animal; Dopaminergic Neurons; Humans; Parkinson Disease; Substantia Nigra

Parkinson's disease (PD) is a severe neurodegenerative disorder affecting movements. After Alzheimer's disease, it is the most common form of neurodegeneration. PD is characterized by the loss of neurons producing dopamine and by the presence of protein aggregates in the brain, known as Lewy bodies. The main constituent of Lewy bodies is the misfolded form of α-synuclein (αSyn), able to form oligomers and fibrils. In addition to protein aggregation, brain damage induced by oxidative stress, is also a frequent phenomenon in PD. αSyn is able to bind Copper ions in both Cu(II) and Cu(I) oxidation states. The metal binding is also maintained when αSyn interacts with membranes. Interestingly, copper binding to αSyn has strong impact either in protein misfolding or in free radical formation, such to provide a link between protein aggregation and oxidative damage. In this review the role of copper and αSyn in PD is discussed with a particular emphasis to elucidate (i) the interaction between copper and αSyn; (ii) the reactivity and (iii) potential toxicity associated with copper-αSyn complexes.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Copper; Humans; Oxidation-Reduction; Oxidative Stress; Parkinson Disease

Epigenetic processes control the embryonic development into multicellular organisms and determine the functional differences of genetically identical cells and individuals. They are also involved in a variety of complex functions such as learning and memory consolidation and have been implicated in aging processes. Beyond the actual genetic information encoded in the DNA sequence, epigenetic modifications in particular DNA methylation and various histone modifications shape the chromatin into a transcriptional permissive or repressive state. DNA methylation patterns are altered by environmental conditions and can be carried forward through mitosis and meiosis. Hence, DNA methylation probably mediates complex environment-gene interactions, determines individual disease characteristics, and contributes to effects and side effects of drugs. In addition to classic monogenic epigenetic diseases, i.e., Prader-Willi and Rett syndrome, recent data point to an epigenetic component also in apparent sporadic neuro-psychiatric disorders and increasing evidence suggests a role for altered DNA methylation in Parkinson's disease. Epigenetic alterations, DNA methylation in particular, may account for the yet unexplained individual susceptibility and the variability in the course of Parkinson's disease and could provide hints toward the development of novel therapeutic targets. Parkinson's disease (PD) is conceptualized as a consequence of genetic variants and environment-gene interactions on a background of age-related changes. Epigenetic modifications have been implicated in aging and can be altered by environment stimuli. The review explores the possibility of an epigenetic component in PD, focusing on DNA methylation. Methylation of α-synuclein (SNCA) and microtubule-associated protein tau gene appear to be of particular importance and epigenome-wide methylation studies point to several additional candidate genes which may contribute to the individual susceptibility toward PD. This article is part of a special issue on Parkinson disease.

Topics: Aging; alpha-Synuclein; Animals; DNA Methylation; Epigenesis, Genetic; Humans; Parkinson Disease; Ubiquitin-Protein Ligases

Approximately 15 % of PD patients with Parkinson Disease (PD) have the familial type and 5-10 % of these are known to have monogenic forms with either an autosomal dominant or a recessive inheritance pattern. Here, we report on a family carrying the A53T SNCA mutation and we review SNCA mutation phenotypes by comparing point mutations within each other as well as with duplication and triplication.

Topics: alpha-Synuclein; Family; Female; Genetic Predisposition to Disease; Humans; Middle Aged; Mutation; Parkinson Disease; Phenotype

A large body of research has been dedicated to the effects of gastrointestinal peptides on vagal afferent fibres, yet multiple lines of evidence indicate that gastrointestinal peptides also modulate brainstem vagal neurocircuitry, and that this modulation has a fundamental role in the physiology and pathophysiology of the upper gastrointestinal tract. In fact, brainstem vagovagal neurocircuits comprise highly plastic neurons and synapses connecting afferent vagal fibres, second order neurons of the nucleus tractus solitarius (NTS), and efferent fibres originating in the dorsal motor nucleus of the vagus (DMV). Neuronal communication between the NTS and DMV is regulated by the presence of a variety of inputs, both from within the brainstem itself as well as from higher centres, which utilize an array of neurotransmitters and neuromodulators. Because of the circumventricular nature of these brainstem areas, circulating hormones can also modulate the vagal output to the upper gastrointestinal tract. This Review summarizes the organization and function of vagovagal reflex control of the upper gastrointestinal tract, presents data on the plasticity within these neurocircuits after stress, and discusses the gastrointestinal dysfunctions observed in Parkinson disease as examples of physiological adjustment and maladaptation of these reflexes.

Topics: Afferent Pathways; alpha-Synuclein; Corticotropin-Releasing Hormone; Efferent Pathways; Gastrointestinal Hormones; Gastrointestinal Motility; Humans; Neuronal Plasticity; Neurotransmitter Agents; Parkinson Disease; Receptors, Oxytocin; Reflex; Stress, Physiological; Vagus Nerve

Therapeutic agents are urgently required to cure several common and fatal neurodegenerative disorders caused by protein misfolding and aggregation, including amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD). Protein disaggregases that reverse protein misfolding and restore proteins to native structure, function, and localization could mitigate neurodegeneration by simultaneously reversing 1) any toxic gain of function of the misfolded form and 2) any loss of function due to misfolding. Potentiated variants of Hsp104, a hexameric AAA+ ATPase and protein disaggregase from yeast, have been engineered to robustly disaggregate misfolded proteins connected with ALS (e.g., TDP-43 and FUS) and PD (e.g., α-synuclein). However, Hsp104 has no metazoan homologue. Metazoa possess protein disaggregase systems distinct from Hsp104, including Hsp110, Hsp70, and Hsp40, as well as HtrA1, which might be harnessed to reverse deleterious protein misfolding. Nevertheless, vicissitudes of aging, environment, or genetics conspire to negate these disaggregase systems in neurodegenerative disease. Thus, engineering potentiated human protein disaggregases or isolating small-molecule enhancers of their activity could yield transformative therapeutics for ALS, PD, and AD.

Topics: alpha-Synuclein; Animals; DNA-Binding Proteins; Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Neurodegenerative Diseases; Parkinson Disease; Protein Aggregates; Protein Engineering; Protein Folding; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins

We describe evidence supporting the hypothesis that α-synuclein has a prion-like role in Parkinson's disease and related α-synucleinopathies, and discuss how this novel thinking impacts the development of diagnostics and disease-modifying therapies.. Observations that immature dopamine neurons grafted to Parkinson's disease patients can develop Lewy bodies triggered a surge of interest in the putative prion-like properties of α-synuclein. We recount results from experiments which confirm that misfolded α-synuclein can exhibit disease-propagating properties, and describe how they relate to the spreading of α-synuclein aggregates in α-synucleinopathies. We share insights into the underlying molecular mechanisms and their relevance to novel therapeutic targets. Finally, we discuss what the initial triggers of α-synuclein misfolding might be, where in the body the misfolding events might take place, and how this can instruct development of novel diagnostic tools. We speculate that differences in anatomical trigger sites and variability in α-synuclein fibril structure can contribute to clinical differences between α-synucleinopathies.. The realization that α-synuclein pathology can propagate between brain regions in neurodegenerative diseases has deepened and expanded our understanding of potential pathogenic processes which can lead to the development of novel diagnostic tools as well as the identification of new therapeutic targets.

Topics: alpha-Synuclein; Humans; Parkinson Disease; Prion Diseases; Prions; Protein Folding

In recent years progress has been made in the detection and evaluation of nonmotor symptoms in Parkinson's disease. The pathophysiology is better understood and new treatment is available, which will be discussed in this review.. The most intriguing recent finding is the fact that Parkinson's disease may be a spreading disease. From the environment a toxin, bacteria, or virus may start in genetically susceptible patients a cascade of α-synuclein aggregation which reaches via the olfactory and the enteric system of the gut the brain where further spreading causes symptoms, such as sleep disturbances, motor impairment, and neuropsychiatric symptoms. New treatment should address the abnormal α-synuclein folding. If this would be achieved premotor signs, such as hyposmia, rapid eye movement-sleep behavior disorder, constipation, or depression may be a kind of biomarkers which allow together with other diagnostic tools, such as parenchymal sonography, iodobenzamide-scintigraphy and dopamine transporter scans the prediction whether somebody might be under way to develop the full-blown Parkinson's disease syndrome.. Parkinson's disease seems to be a spreading disease which causes not only a dopaminergic deficit as major cause for the movement disorder but also impairs function of many other brain centers which leads to a multitransmitter malfunction.

Topics: alpha-Synuclein; Autonomic Nervous System Diseases; Cardiovascular Diseases; Dyskinesias; Early Diagnosis; Erectile Dysfunction; Fatigue; Gastrointestinal Diseases; Humans; Male; Mental Disorders; Movement Disorders; Olfaction Disorders; Pain; Parkinson Disease; Sleep Wake Disorders; Urologic Diseases

The diagnostic criteria currently used for Parkinson's disease (PD) are mainly based on clinical motor symptoms. For these reasons many biomarkers are under investigation to support the diagnosis at the early stage. The neuropathological hallmark of PD is represented by Lewy bodies (LBs), which are intracytoplasmic inclusions in substantia nigra neurons. The major component of LBs, α-synuclein (α-syn), has been implicated in the pathogenesis of PD and in other 'synucleinopathies' such as multisystem atrophy (MSA) and dementia with LBs (DLBs). Several studies have investigated this presynaptic protein as a potential biomarker of PD. The aim of our meta-analysis is to determine the ability of cerebrospinal fluid (CSF) concentrations of total α-syn, oligomeric α-syn and phosphorylated α-syn to discriminate patients with PD from healthy participants, non-degenerative neurological controls and patients suffering from parkinsonism and or synucleinopathies.. This systematic review protocol has been developed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol (PRISMA-P) 2015 statement and was registered on PROSPERO (CRD42016013217). We will search Cochrane Library, Web of Science, MEDLINE (via PubMed) and EMBASE from inception, using appropriate search strategies. Two independent reviewers will screen titles, abstracts and full-text articles, and will complete data abstraction. We will include studies that involved patients with PD, DLB, MSA, progressive supranuclear palsy, corticobasal disease and vascular PD, and in which at least one between total α-syn, oligomeric α-syn and phosphorylated α-syn was measured in CSF. To evaluate the risk of bias and applicability of primary diagnostic accuracy studies, we will use QUADAS-2.. Our study will not include confidential data, and no intervention will be involved, so ethical approval is not required. The results of the study will be reported in international peer-reviewed journals.

Topics: alpha-Synuclein; Biomarkers; Diagnosis, Differential; Humans; Lewy Bodies; Multiple System Atrophy; Parkinson Disease; Research Design; Systematic Reviews as Topic

The missense mutation A53T of alpha-synuclein gene (SNCA) was reported to be a rare but definite cause of sporadic and familial Parkinson disease (PD). It seemed to be restricted geographically in Greece and Italy. We aimed to identify the SNCA mutations in a Chinese PD cohort. Ninety-one early onset PD patients or familial PD probands were collected consecutively for the screening of PD-related genes. The genetic analysis was carried out by target sequencing of the exons and the corresponding flanking regions of the PD-related genes using Illumina HiSeq 2000 sequencer and further confirmed by Sanger sequencing or restriction fragment length polymorphism. Dosage mutations of exons in these genes were carried out by multiple ligation-dependent probe amplification. Among the 91 patients, we found only one heterozygous mutation of SNCA A53T, in a 23-year-old male patient with negative family history. The [(11)C]-2β-carbomethoxy-3β-(4-fluorophenyl) tropan (CFT) PET and PD-related spatial covariance pattern (PDRP) via [(18)F]-fluorodeoxyglucos (FDG) PET confirmed a typical pattern of PD. After examining his parents, we found his mother was an asymptomatic carrier, with declined hand dexterity detected by quantitative motor tests. Reduced dopamine transporter uptake of his mother was identified by CFT PET, and abnormal PDRP pattern was found by FDG PET. Our investigation expanded the clinical and genetic spectrum of Chinese PD patients, and we suggested SNCA mutations to be screened in familial and early onset Chinese PD patients.

Topics: Adolescent; Adult; Aged; alpha-Synuclein; Child; China; DNA Mutational Analysis; Dopamine Plasma Membrane Transport Proteins; Female; Genotype; Heterozygote; Humans; Male; Middle Aged; Mutation; Parkinson Disease; Positron-Emission Tomography; Young Adult

Parkinson's disease (PD) is a common neurodegenerative disorder associated with aging. Great progresses have been made toward understanding the pathogenesis over the past decades. It seems that both genetic factors and environmental factors contribute to PD, while the precise pathogenesis still remains unknown. Recently, increasing evidence has suggested that autophagy dysregulation is closely related to PD. Dysregulation of the autophagic pathways has been observed in the brains of PD patients or in animal models of PD, and a number of PD-associated proteins, such as a-synuclein, Parkin and PINK1, were found to involve in autophagy, suggesting a link between autophagy and pathogenesis of PD. In this review, we summarized the role of PD-associated proteins in autophagy pathways. In addition, we described the efficacy of autophagy-modulating compounds in PD models and discussed promising strategies for PD therapy.

Topics: alpha-Synuclein; Animals; Autophagy; Humans; Parkinson Disease; Protein Kinases; Ubiquitin-Protein Ligases

Early involvement of gut is observed in Parkinson's disease (PD) and symptoms such as constipation may precede motor symptoms. α-Synuclein pathology is extensively evident in the gut and appears to follow a rostrocaudal gradient. The gut may act as the starting point of PD pathology with spread toward the central nervous system. This spread of the synuclein pathology raises the possibility of prion-like propagation in PD pathogenesis. Recently, the role of gut microbiota in PD pathogenesis has received attention and some phenotypic correlation has also been shown. The extensive involvement of the gut in PD even in its early stages has led to the evaluation of enteric α-synuclein as a possible biomarker of early PD. The clinical manifestations of gastrointestinal dysfunction in PD include malnutrition, oral and dental disorders, sialorrhea, dysphagia, gastroparesis, constipation, and defecatory dysfunction. These conditions are quite distressing for the patients and require relevant investigations and adequate management. Treatment usually involves both pharmacological and non-pharmacological measures. One important aspect of gut dysfunction is its contribution to the clinical fluctuations in PD. Dysphagia and gastroparesis lead to inadequate absorption of oral anti-PD medications. These lead to response fluctuations, particularly delayed-on and no-on, and there is significant relationship between levodopa pharmacokinetics and gastric emptying in patients with PD. Therefore, in such cases, alternative routes of administration or drug delivery systems may be required.

Topics: alpha-Synuclein; Antiparkinson Agents; Constipation; Deglutition Disorders; Enteric Nervous System; Gastrointestinal Absorption; Gastrointestinal Microbiome; Gastrointestinal Tract; Gastroparesis; Humans; Malnutrition; Parkinson Disease; Sialorrhea

α-Synuclein, which is present as a small, soluble, cytosolic protein in healthy subjects, is converted to amyloid-like fibrils in diseases such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Bulk synthesis of purified α-synuclein has made it more convenient to study the nature of the normal protein and the mechanism of its conversion to an abnormal form in vitro and in vivo. Synthetic α-synuclein fibrils and pathological α-synuclein from diseased brains can act as triggers to convert normal α-synuclein to an abnormal form via prion-like mechanisms. In this article, we describe the experimental pathologies of α-synuclein both in vitro and in vivo in human and animal models. Prion-like spreading of abnormal α-synuclein from cell to cell can account for the progression of these α-synucleinopathies.

Topics: alpha-Synuclein; Amyloid; Animals; Brain; Disease Models, Animal; Disease Progression; Humans; Lewy Body Disease; Mice; Multiple System Atrophy; Parkinson Disease

Experimental data indicate that transneuronal propagation of abnormal protein aggregates in neurodegenerative proteinopathies, such as sporadic Alzheimer's disease (AD) and Parkinson's disease (PD), is capable of a self-propagating process that leads to a progression of neurodegeneration and accumulation of prion-like particles. The mechanisms by which misfolded tau and α-synuclein possibly spread from one involved nerve cell to the next in the neuronal chain to induce abnormal aggregation are still unknown. Based on findings from studies of human autopsy cases, we review potential pathways and mechanisms related to axonal and transneuronal dissemination of tau (sporadic AD) and α-synuclein (sporadic PD) aggregates between anatomically interconnected regions.

Topics: alpha-Synuclein; Alzheimer Disease; Humans; Parkinson Disease; tau Proteins

Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are characterised by abnormal neuroglial α-synuclein accumulation. These α-synucleinopathies have in common parkinsonism and non-motor features including orthostatic hypotension (OH) and cognitive impairment. However, the nature of the relationship between OH and cognitive impairment is unclear. We therefore systematically reviewed the literature for evidence of an association between OH and cognitive impairment in α-synucleinopathies and discuss possible mechanisms and implications of this relationship. Abstracts from 313 original research articles were surveyed, and a total of 132 articles were considered for this review. Articles were stratified as: 'direct-evidence studies' based on the direct assessment for a relationship between OH and cognitive impairment in α-synucleinopathies, and 'indirect-evidence studies' based on an association being referred to as a secondary outcome. Ten 'direct-evidence papers' were identified, seven of which reported a positive association between OH and cognitive impairment, while seven of 12 'indirect-evidence papers' similarly did as well. The papers that reported no association between OH and cognitive impairment used less sensitive measures of cognition. A relationship between OH and cognitive impairment in patients with α-synucleinopathies exists, but the underlying mechanisms remain unclear. Three hypotheses are proposed: (1) OH and cognitive impairment occur concurrently due to diffuse brain and peripheral deposition of α-synuclein, (2) OH-mediated cerebral hypoperfusion impairs cognition and (3) the two act synergistically to accelerate cognitive decline. Longitudinal neuroimaging studies and clinical trials may help clarify the nature of this relationship.

Topics: alpha-Synuclein; Cerebral Small Vessel Diseases; Cognitive Dysfunction; Humans; Hypotension, Orthostatic; Hypoxia-Ischemia, Brain; Lewy Body Disease; Longitudinal Studies; Magnetic Resonance Imaging; Mental Status Schedule; Multiple System Atrophy; Neuroglia; Parkinson Disease; Positron Emission Tomography Computed Tomography; Risk Factors; Statistics as Topic

Lysosomal dysfunction has been implicated in multiple diseases, including lysosomal storage disorders such as Gaucher's disease, in which loss-of-function mutations in the GBA1 gene encoding the lysosomal hydrolase β-glucocerebrosidase result in lipid substrate accumulation. In Parkinson's disease, α-synuclein accumulates in Lewy bodies and neurites contributing to neuronal death. Previous clinical and genetic evidence has demonstrated an important link between Parkinson's and Gaucher's disease, as GBA1 mutations and variants increase the risk of Parkinson's and Parkinson's patients exhibit decreased β-glucocerebrosidase activity. Using human midbrain neuron cultures, we have found that loss of β-glucocerebrosidase activity promotes α-synuclein accumulation and toxicity, whereas α-synuclein accumulation further contributes to decreased lysosomal β-glucocerebrosidase activity by disrupting β-glucocerebrosidase trafficking to lysosomes. Moreover, α-synuclein accumulation disrupts trafficking of additional lysosomal hydrolases, further contributing to lysosomal dysfunction and neuronal dyshomeostasis. Importantly, promoting β-glucocerebrosidase activity reduces α-synuclein accumulation and rescues lysosomal and neuronal dysfunction, suggesting that β-glucocerebrosidase may be an important therapeutic target for advancing drug discovery in synucleinopathies including Parkinson's disease. © 2016 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Gaucher Disease; Glucosylceramidase; Humans; Lysosomes; Parkinson Disease

Tau and α-Synuclein (α-Syn) are abundant brain proteins with distinct biological functions. Findings suggest that interactions between α-Syn and tau at the cellular level cause disruption of cytoskeletal organization, axonal transport defects, and aberrant synaptic organization. The ability of tau and α-Syn to affect each other directly or indirectly might contribute to the overlap in the clinical and pathological features of tauopathies and synucleinopathies. The interactions between α-Syn and tau, and the underlying molecular pathogenic mechanisms, including induction and spread of protein aggregates, still deserve further investigation.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Humans; Parkinson Disease; Protein Binding; Protein Processing, Post-Translational; Synapses; tau Proteins

Parkinson's disease (PD) is a devastating and progressive movement disorder characterized by symptoms of muscles rigidity, tremor, postural instability and slow physical movements. Biochemically, PD is characterized by lack of dopamine production and its action due to loss of dopaminergic neurons and neuropathologically by the presence of intracytoplasmic inclusions known as Lewy bodies, which mainly consist of presynaptic neuronal protein, α-synuclein (α-syn). It is believed that alteration in α-syn homeostasis leads to increased accumulation and aggregation of α-syn in Lewy body. Based on the important role of α-syn from pathogenesis to therapeutics, the recent researches are mainly focused on deciphering the critical role of α-syn at advanced level. Being a major protein in Lewy body that has a key role in pathogenesis of PD, several model systems including immortalized cell lines (SH-SY5Y), primary neuronal cultures, yeast (saccharomyces cerevisiae), drosophila (fruit flies), nematodes (Caenorhabditis elegans) and rodents are being employed to understand the PD pathogenesis and treatment. In order to study the etiopathogensis and develop novel therapeutic target for α -syn aggregation, majority of investigators rely on toxin (rotenone, 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine, 6-hydroxydopamine, paraquat)-induced animal models of PD as a tool for basic research. Whereas, cell and tissue based models are mostly utilized to elucidate the mechanistic and molecular pathways underlying the α -syn induced toxicity and therapeutic approaches in PD. Gene modified mouse models based on α-syn expression are fascinating for modeling familial PD and toxin induced models provide a suitable approach for sporadic PD. The purpose of this review is to provide a summary and a critical review of the involvement of α-syn in various in vitro and in vivo models of PD based on use of neurotoxins as well as genetic modifications.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Humans; Lewy Bodies; Neurons; Neurotoxins; Parkinson Disease

The therapeutic management of Parkinson's disease (PD) is challenging and has not been fully resolved. The main challenges include motor fluctuations and levodopa-induced dyskinesia. Moreover, no disease-modifying or neuroprotective therapy is currently available. Areas covered: This review focuses on α-synuclein aggregation inhibitors and their therapeutic role in PD, with special attention to heat shock proteins, immunotherapy (active and passive), the potential of targeting the Ser129 phosphorylation site, and the antibiotic possibilities. Expert opinion: The induction of chaperones may provide beneficial strategy to target synucleinopathies, but further investigations are needed to find the best options. The promising preclinical results with immunotherapy suggest that it may be a valuable disease-modifying therapy in PD in the future. Clinical trials are currently in the initial phases, and future studies need to confirm the beneficial therapeutic effect in humans and clarify open questions as regards the exact mode of action and potential safety concerns. In case of covalent modifications, phosphorylation of α-synuclein is of outstanding importance; however, conflicting results and open questions exist which necessitate clarification. In vitro results suggest that several antibiotics may also influence α-synuclein aggregation, but these results are to be confirmed in the future.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Drug Design; Drugs, Investigational; Humans; Immunotherapy; Molecular Chaperones; Parkinson Disease

The mechanisms underlying the high prevalence of cutaneous malignant melanoma (CMM) in Parkinson disease (PD) are unclear, but plausibly involve common pathways. 129Ser-phosphorylated α-synuclein, a pathological PD hallmark, is abundantly expressed in CMM, but not in normal skin. In inherited PD, PARK genes harbor germline mutations; the same genes are somatically mutated in CMM, or their encoded proteins are involved in melanomagenesis. Conversely, genes associated with CMM affect PD risk. PD/CMM-targeted cells share neural crest origin and melanogenesis capability. Pigmentation gene variants may underlie their susceptibility. We review putative genetic intersections that may be suggestive of shared pathways in neurodegeneration/melanomagenesis. Ann Neurol 2016;80:811-820.

Topics: alpha-Synuclein; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p18; Genetic Predisposition to Disease; Genotype; Humans; Melanoma; Melanoma, Cutaneous Malignant; Parkinson Disease; Parkinson Disease Associated Proteins; Polymorphism, Single Nucleotide; Receptor, Melanocortin, Type 1; Receptors, N-Methyl-D-Aspartate; Skin Neoplasms

In recent years, a new generation of animal models of Parkinson's disease (PD) based on ectopic expression, overexpression, or intracerebral injection of the protein α-synuclein have emerged. Critically, these models develop inclusions of aggregated α-synuclein and/or α-synuclein-mediated neuronal loss replicating the defining pathological hallmarks of PD and driving significant advances in the understanding of the pathogenic mechanisms underpinning PD. Here, we provide a comprehensive review of this new generation of animal models of PD, ranging from invertebrate to rodent to nonhuman primate. We focus on their strengths and limitations with respect to their highly anticipated contribution to the further understanding of α-synuclein pathobiology and the future testing of novel disease-modifying therapeutics.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Drug Discovery; Humans; Neurons; Parkinson Disease; Prions

Almost two decades after the identification of SNCA as the first causative gene in Parkinson's disease (PD) and the subsequent understanding that genetic factors play a substantial role in PD development, our knowledge of the genetic architecture underlying this disease has vastly improved. Approximately 5-10% of patients suffer from a monogenic form of PD where autosomal dominant mutations in SNCA, LRRK2, and VPS35 and autosomal recessive mutations in PINK1, DJ-1, and Parkin cause the disease with high penetrance. Furthermore, recent whole-exome sequencing have described autosomal recessive DNAJC6 mutations in predominately atypical, but also cases with typical PD. In addition, several other genes have been linked to atypical Parkinsonian phenotypes. However, the vast majority of PD is genetically complex, i.e. it is caused by the combined action of common genetic variants in concert with environmental factors. By the application of genome-wide association studies, 26 PD risk loci have been established to date. Similar to other genetically complex diseases, these show only moderate effects on PD risk. Increasing this etiologic complexity, many of the involved genetic and environmental risk factors likely interact in an intricate fashion. This article aims to provide a comprehensive overview of the current knowledge in PD genetics.

Topics: alpha-Synuclein; Gene-Environment Interaction; Genetic Association Studies; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Parkinson Disease; Polymorphism, Single Nucleotide; Risk Factors; Ubiquitin-Protein Ligases

Parkinson's disease is a debilitating, age-associated movement disorder. A central aspect of the pathophysiology of Parkinson's disease is the progressive demise of midbrain dopamine neurons and their axonal projections, but the underlying causes of this loss are unclear. Advances in genetics and experimental model systems have illuminated an important role for defects in intracellular transport pathways to lysosomes. The accumulation of altered proteins and damaged mitochondria, particularly at axon terminals, ultimately might overwhelm the capacity of intracellular disposal mechanisms. Cell-extrinsic mechanisms, including inflammation and prion-like spreading, are proposed to have both protective and deleterious functions in Parkinson's disease.

Topics: alpha-Synuclein; Animals; Biological Transport; Endocytosis; Glucosylceramidase; Humans; Inflammation; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lysosomes; Models, Biological; Molecular Targeted Therapy; Neurons; Parkinson Disease; Prions; Synaptic Vesicles

Neurodegenerative diseases are a major public health issue worldwide. Some countries, including France, have engaged in research into the causes of Parkinson's disease, Alzheimer's disease, and multiple sclerosis and the management of these patients. It should lead to a better understanding of the mechanisms leading to these diseases including the possible involvement of lipids in their pathogenesis. Parkinson's disease is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein (Lewy bodies). Several in vivo studies have shown a relationship between the lipid profile [cholesterol, oxidized cholesterol products (oxysterols) formed either enzymatically or by auto-oxidation], the use of drugs regulating cholesterol levels, and the development of Parkinson's disease. Several oxysterols are present in the brain and could play a role in the development of this disease, particularly in the accumulation of α-synuclein, and through various side effects, such as oxidation, inflammation, and cell death. Consequently, in Parkinson's disease, some oxysterols could contribute to the pathophysiology of the disease and constitute potential biomarkers or therapeutic targets.

Topics: alpha-Synuclein; Cell Death; Cholesterol; Dopaminergic Neurons; Humans; Oxidation-Reduction; Oxysterols; Parkinson Disease; Presynaptic Terminals; Protein Aggregates; Substantia Nigra

Aggregation of α-Synuclein (α-Syn) into amyloid fibrils is known to be associated with the pathogenesis of Parkinson's disease (PD). Several missense mutations of the α-Syn gene have been associated with rare, early onset familial forms of PD. Despite several studies done so far, the local/residue-level structure and dynamics of α-Syn in its soluble and aggregated fibril form and how these are affected by the familial PD associated mutations are still not clearly understood. Here, we review studies performed by our group as well as other research groups, where time-resolved fluorescence spectroscopy has been used to understand the site-specific structure and dynamics of α-Syn under physiological conditions as well as under conditions that alter the aggregation properties of the protein such as low pH, high temperature, presence of membrane mimics and familial PD associated mutations. These studies have provided important insights into the critical structural properties of α-Syn that may govern its aggregation. The review also highlights time-resolved fluorescence as a promising tool to study the critical conformational transitions associated with early oligomerization of α-Syn, which are otherwise not accessible using other commonly used techniques such as thioflavin T (ThT) binding assay.

Topics: alpha-Synuclein; Amyloid; Humans; Mutation, Missense; Parkinson Disease; Spectrometry, Fluorescence

In order to study the molecular pathways of Parkinson's disease (PD) and to develop novel therapeutic strategies, scientific investigators rely on animal models. The identification of PD-associated genes has led to the development of genetic PD models as an alternative to toxin-based models. Viral vector-mediated loco-regional gene delivery provides an attractive way to express transgenes in the central nervous system. Several vector systems based on various viruses have been developed. In this chapter, we give an overview of the different viral vector systems used for targeting the CNS. Further, we describe the different viral vector-based PD models currently available based on overexpression strategies for autosomal dominant genes such as α-synuclein and LRRK2, and knockout or knockdown strategies for autosomal recessive genes, such as parkin, DJ-1, and PINK1. Models based on overexpression of α-synuclein are the most prevalent and extensively studied, and therefore the main focus of this chapter. Many efforts have been made to increase the expression levels of α-synuclein in the dopaminergic neurons. The best α-synuclein models currently available have been developed from a combined approach using newer AAV serotypes and optimized vector constructs, production, and purification methods. These third-generation α-synuclein models show improved face and predictive validity, and therefore offer the possibility to reliably test novel therapeutics.

Topics: alpha-Synuclein; Animals; Dependovirus; Disease Models, Animal; Genetic Vectors; Lentivirus; Parkinson Disease

Parkinson's disease (PD) is the most prevalent neurodegenerative movement disorder. Genetic studies over the past two decades have greatly advanced our understanding of the etiological basis of PD and elucidated pathways leading to neuronal degeneration. Recent studies have suggested that abnormal autophagy, a well conserved homeostatic process for protein and organelle turnover, may contribute to neurodegeneration in PD. Moreover, many of the proteins related to both autosomal dominant and autosomal recessive PD, such as α-synuclein, PINK1, Parkin, LRRK2, DJ-1, GBA, and ATPA13A2, are also involved in the regulation of autophagy. We propose that reduced autophagy enhances the accumulation of α-synuclein, other pathogenic proteins, and dysfunctional mitochondria in PD, leading to oxidative stress and neuronal death.

Topics: alpha-Synuclein; Animals; Autophagy; Humans; Lysosomes; Mitophagy; Models, Biological; Parkinson Disease

Parkinson's disease (PD) is mainly attributed to degeneration of dopamine neurons in the substantia nigra, but its etiopathogenesis also includes impaired protein clearance and axonal transport dysfunction, among others. The spread of α-synuclein (α-syn) aggregates from one neuron to another, in a prion-like manner, is hypothesized to contribute to PD progression. Axonal transport is likely to play a crucial role in this movement of α-syn aggregates between brain regions. At the same time, deficits in axonal transport are suggested to contribute to neuronal failure in PD. In this review, we discuss the apparent contradiction that axonal transport might be essential for disease progression, while dysfunction of axonal transport could simultaneously be a cornerstone of PD pathogenesis. We speculate around models that reconcile how axonal transport can play such a paradoxical role.

Topics: alpha-Synuclein; Animals; Axonal Transport; Humans; Mitochondrial Diseases; Neuroglia; Parkinson Disease

α-Synuclein, an abundant and conserved presynaptic brain protein, is implicated as a critical factor in Parkinson's disease (PD). The aggregation of α-synuclein is believed to be a critical event in the disease process. α-Synuclein is characterized by a remarkable conformational plasticity, adopting different conformations depending on the environment. Therefore, it is classified as an "intrinsically disordered protein." Recently, a debate has challenged the view on the intrinsically disordered behavior of α-synuclein in the cell. It has been proposed that α-synuclein is a stable tetramer with a low propensity for aggregation; however, its destabilization leads to protein misfolding and its aggregation kinetics. In our critical analysis, we discussed about major issues: (i) why α-synuclein conformational behavior does not fit into the normal secondary structural characteristics of proteins, (ii) potential amino acids involved in the complexity of misfolding in α-synuclein that leads to aggregation, and (iii) the role of metals in misfolding and aggregation. To evaluate the above critical issues, we developed bioinformatics models related to secondary and tertiary conformations, Ramachandran plot, free energy change, intrinsic disordered prediction, solvent accessibility, and FoldIndex pattern. To the best of our knowledge, this is a novel critical assessment to understand the misfolding biology of synuclein and its relevance to Parkinson's disease.

Topics: alpha-Synuclein; Animals; Humans; Kinetics; Parkinson Disease; Protein Conformation; Protein Folding; Protein Structure, Secondary

The pathological hallmark of Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies (LBs). LBs are intracellular inclusions typically found in these neurons and in noradrenergic neurons of the locus coeruleus in patients with PD. However, LBs can be found more widely in neurons of the olfactory bulb, cerebral cortex, and spinal cord. Additionally, LBs appear in neurons of the cardiac, cutaneous, and intestinal autonomic nervous systems. LBs are composed of fibrillar aggregates of α-synuclein (α-syn). The widespread distribution of LBs indicates that α-syn aggregation occurs in neurons in various areas, supporting the concept that PD is not only a simple movement disorder but also a complex one with nonmotor impairments. However, it is unclear how α-syn pathology spreads in the nervous system. Postmortem analyses of patients with PD who received transplants of fetal mesencephalic dopaminergic neurons revealed LB formation in surviving grafts, providing a crucial clue regarding the host-to-graft disease propagation. Recent experiments demonstrated that fibrillar α-syn is transferred from neurons to neurons in cellular and animal models, suggesting that fibrillar α-syn is repeatedly generated in cells by triggering the continuous conversion of normal soluble species into fibrillar ones. These findings suggest a "prion-like" mechanism for α-syn propagation in the pathogenesis of PD. This review summarizes the experimental findings on the prion-like propagation of α-syn and discusses the potential of cellular and animal models for testing the protective effects of chemical agents against neurodegeneration in PD.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Disease Models, Animal; Humans; Models, Biological; Parkinson Disease; Prions

To date, there are no definitive biomarkers for Parkinson's disease (PD) diagnosis. The detection of cerebrospinal fluid (CSF) alpha (α)-synuclein in PD patients has yielded promising but inconclusive results. To determine the performance of CSF α-synuclein as a diagnostic biomarker of PD and whether CSF α-synuclein can discriminate PD from other neurodegenerative diseases, a systematic search of all relevant studies investigating reproducible CSF α-synuclein quantification methods was conducted in electronic databases. A total of 17 studies that included 3311 patients were included in this systemic review and meta-analysis. The mean CSF α-synuclein concentration was significantly lower in PD patients compared to normal/neurological controls [weighted mean difference (WMD) -0.31; 95% CI, -0.45, -0.16; p < 0.0001] and patients with Alzheimer's disease (AD) [WMD -0.15; 95% CI, -0.26, -0.04; p < 0.0001]. There was no significant difference between PD patients and dementia with Lewy bodies (DLB) patients [WMD -0.03; 95% CI, -0.16, 0.09; p = 0.58] or patients with multiple system atrophy (MSA) [WMD 0.05; 95% CI, -0.04, 0.13; p = 0.25]. Sensitivity and specificity of CSF α-synuclein in the diagnosis of PD was 0.88 (95% CI, 0.84-0.91) and 0.40 (95% CI, 0.35-0.45), respectively. The positive and negative likelihood ratios of CSF α-synuclein in the diagnosis of PD were 1.41 (95% CI, 1.24-1.60), and 0.29 (95% CI, 0.15-0.56), respectively. The corresponding summary receiver operating characteristic (SROC) curve showed an area under the curve (AUC) of 0.73. The concentration of CSF α-synuclein may be a biomarker for the diagnosis of PD. The use of α-synuclein alone however is not sufficient as a single biomarker and it must therefore be used in conjunction with other documented and reliable biomarkers.

Topics: alpha-Synuclein; Biomarkers; Humans; Parkinson Disease

The aggregation of alpha-synuclein (aSyn) has been implicated in a number of degenerative diseases collectively termed synucleinopathies. Although most cases of synucleinopathies are idiopathic in nature, there are familial cases of these diseases that are due to mutations or multiplications of the gene coding for aSyn. Two of the most common synucleinopathies are Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Both of these diseases present with cognitive deficits, though with different clinical and temporal features. In PD, cognitive deficits are subtle, may occur before the onset of the classical motor symptoms, and only occasionally lead to dementia in the later stages of the disease. In contrast, dementia is the dominating feature of DLB from the disease onset. The impact of aSyn pathology on the development of neurobiological and behavioral impairments can be investigated using rodent models. There are currently several lines of transgenic mice overexpressing wild-type or mutated aSyn under various promoters. This review will provide an updated synopsis of the mouse lines available, summarize their cognitive deficits, and reflect on how deficits observed in these mice relate to the disease process in humans. In addition, we will review mouse lines where knockout strategies have been applied to study the effects of aSyn on various cognitive tasks and comment on how these lines have been used in combination with other transgenic strains, or with human aSyn overexpression by viral vectors. Finally, we will discuss the recent advent of bacterial artificial chromosome (BAC) transgenic models of PD and their effectiveness in modeling cognitive decline in PD.

Topics: alpha-Synuclein; Animals; Animals, Genetically Modified; Cognition Disorders; Dementia; Disease Models, Animal; Mice; Parkinson Disease; Rats

Parkinson's disease is a chronic, progressive neurodegenerative disorder with increased prevalence in the aging population. It is estimated that approximately 1.5 million individuals in the US alone suffer from Parkinson's disease and with the extension of life expectancy this number is expected to rise dramatically within the next twenty-five years. The majority of Parkinson's disease cases are sporadic. But mutations in genes such as α-synuclein, Parkin, PINK1, DJ-1 and LRRK2, have been conclusively associated with both early- and late-onset of the disease. Although the genetics of Parkinson's disease is starting to become unraveled, the interplay between genetic and environmental factors is largely unknown as are the underlying mechanisms that trigger the disease as the brain ages. The risk of Parkinson's disease increases dramatically in individuals over the age of 60 and it is estimated that more than 1% of all seniors have some form of the condition. In this review, we will highlight some of the central proteins associated with Parkinson's disease and how they may be linked to processes and factors associated with age.

Topics: Aging; alpha-Synuclein; Autophagy; Cell Death; Environment; Humans; Intracellular Signaling Peptides and Proteins; Late Onset Disorders; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mitophagy; Neurons; Oncogene Proteins; Oxidative Stress; Parkinson Disease; Protein Deglycase DJ-1; Protein Serine-Threonine Kinases

Alzheimer's disease (AD), the most common form of dementia, is characterized histopathologically by the deposition of β-amyloid (Aβ) plaques and neurofibrillary tangles-containing hyperphosphorylated tau protein in the brain. Parkinson's disease (PD), the most common movement disorder, is characterized by the aggregation of α-synuclein protein in Lewy body inclusions and the death of dopaminergic neurons in the substantia nigra. Based on their pathological signatures, AD and PD can be considered as two different disease entities. However, a subpopulation of PD patients also exhibit Aβ plaques, and AD patients exhibit α-synuclein aggregates. This overlap between PD and AD suggests that common pathological pathways exist for the two diseases. Identification of factors and cellular mechanisms by which these factors can trigger pathological hallmarks for AD/PD overlap may help in designing disease-modifying therapies that can reverse or stop the progression of AD and PD. For the last decade, work in our laboratory has shown that fluctuations in the levels of cholesterol oxidation products (oxysterols) may correlate with the onset of AD and PD. In this review, we will provide results from our laboratory and data from literature that converge to strongly suggest the involvement of cholesterol and cholesterol oxidation products in the pathogenesis of AD and PD. We will specifically delineate the role of and the underlying mechanisms by which increased levels of the oxysterol 27-hydroxycholesterol contribute to the pathogenesis of AD, PD, and AD/PD overlap.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Brain; Cholesterol, Dietary; Disease Models, Animal; Endoplasmic Reticulum Stress; Homeostasis; Humans; Hydroxycholesterols; Lipid Metabolism; Liver X Receptors; Orphan Nuclear Receptors; Parkinson Disease; Plaque, Amyloid; Rabbits

The proteins alpha-synuclein (αSyn) and leucine rich repeat kinase 2 (LRRK2) are both key players in the pathogenesis of the neurodegenerative disorder Parkinson's disease (PD), but establishing a functional link between the two proteins has proven elusive. Research studies for these two proteins have traditionally and justifiably focused in neuronal cells, but recent studies indicate that each protein could play a greater pathological role elsewhere. αSyn is expressed at high levels within neurons, but they also secrete the protein into the extracellular milieu, where it can have broad ranging effects in the nervous system and relevance to disease etiology. Similarly, low neuronal LRRK2 expression and activity suggests that LRRK2-related functions could be more relevant in cells with higher expression, such as brain-resident microglia. Microglia are monocytic immune cells that protect neurons from noxious stimuli, including pathological αSyn species, and microglial activation is believed to contribute to neuroinflammation and neuronal death in PD. Interestingly, both αSyn and LRRK2 can be linked to microglial function. Secreted αSyn can directly activate microglia, and can be taken up by microglia for clearance, while LRRK2 has been implicated in the intrinsic regulation of microglial activation and of lysosomal degradation processes. Based on these observations, the present review will focus on how PD-associated mutations in LRRK2 could potentially alter microglial biology with respect to neuronally secreted αSyn, resulting in cell dysfunction and neurodegeneration.

Topics: alpha-Synuclein; Animals; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Microglia; Parkinson Disease; Protein Serine-Threonine Kinases

Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, non-motor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/β-catenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PD-related genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Dopamine; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; MicroRNAs; Neural Stem Cells; Neurogenesis; Parkinson Disease; Protein Serine-Threonine Kinases

The last 2 decades represent a period of unparalleled advancement in the understanding of the pathogenesis of Parkinson disease (PD). The discovery of several forms of familial parkinsonism with mendelian inheritance has elucidated insights into the mechanisms underlying the degeneration of dopaminergic neurons of the substantia nigra that histologically characterize PD. α-Synuclein, the principal component of Lewy bodies, remains the presumed pathogen at the heart of the current model; however, concurrently, a diverse range of other mechanisms have been implicated. The creation of a coherent disease model will be crucial to the development of effective disease modifying therapies for sporadic PD.

Topics: alpha-Synuclein; Glucosylceramidase; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Nerve Degeneration; Parkinson Disease; Protein Serine-Threonine Kinases; Substantia Nigra

Parkinson's disease is one of several neurodegenerative diseases associated with a misfolded, aggregated and pathological protein. In Parkinson's disease this protein is alpha-synuclein and its neuronal deposits in the form of Lewy bodies are considered a hallmark of the disease. In this review we describe the clinical and experimental data that have led to think of alpha-synuclein as a prion-like protein and we summarize data from in vitro, cellular and animal models supporting this view.

Topics: alpha-Synuclein; Animals; Humans; Parkinson Disease; Prions; Protein Folding

Sporadic or idiopathic Parkinson's disease (PD) is an age-related neurodegenerative disorder of unknown origin that ranks only second behind Alzheimer's disease (AD) in prevalence and its consequent social and economic burden. PD neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta; however, more widespread involvement of other CNS structures and peripheral tissues now is widely documented. The onset of molecular and cellular neuropathology of PD likely occurs decades before the onset of the motor symptoms characteristic of PD. The hallmark symptoms of PD, resting tremors, rigidity and postural disabilities, are related to dopamine (DA) deficiency. Current therapies treat these symptoms by replacing or boosting existing DA. All current interventions have limited therapeutic benefit for disease progression because damage likely has progressed over an estimated period of ~5 to 15years to a loss of 60%-80% of the nigral DA neurons, before symptoms emerge. There is no accepted definitive biomarker of PD. An urgent need exists to develop early diagnostic biomarkers for two reasons: (1) to intervene at the onset of disease and (2) to monitor the progress of therapeutic interventions that may slow or stop the course of the disease. In the context of disease development, one of the promises of personalized medicine is the ability to predict, on an individual basis, factors contributing to the susceptibility for the development of a given disease. Recent advances in our understanding of genetic factors underlying or contributing to PD offer the potential for monitoring susceptibility biomarkers that can be used to identify at-risk individuals and possibly prevent the onset of disease through treatment. Finally, the exposome concept is new in the biomarker discovery arena and it is suggested as a way to move forward in identifying biomarkers of neurological diseases. It is a two-stage scheme involving a first stage of exposome-wide association studies (EWAS) to profile omic features in serum to discover molecular biomarkers. The second stage involves application of this knowledge base in follow-up studies. This strategy is unique in that it promotes the use of data-driven (omic) strategies in interrogating diseased and healthy populations and encourages a movement away from using only reductionist strategies to discover biomarkers of exposure and disease. In this short review we will examine 1) advances i

Topics: alpha-Synuclein; Antiparkinson Agents; Apoptosis; Biomarkers; Disease Progression; Dopamine; Early Diagnosis; Humans; Motor Skills; Neuroimaging; Parkinson Disease; Pars Compacta; Predictive Value of Tests; Risk Factors; Sleep, REM; Smell

Alpha-synuclein (α-syn) is central to the pathogenesis of Parkinson disease (PD). Gene duplications, triplications and point mutations in SNCA1, the gene encoding α-syn, cause autosomal dominant forms of PD. Aggregated and post-translationally modified forms of α-syn are present in Lewy bodies and Lewy neurites in both sporadic and familial PD, and recent work has emphasized the prion-like ability of aggregated α-syn to produce spreading pathology. Accumulation of abnormal forms of α-syn is a trigger for PD, but recent evidence suggests that much of the downstream neurodegeneration may result from inflammatory responses. Components of both the innate and adaptive immune systems are activated in PD, and influencing interactions between innate and adaptive immune components has been shown to modify the pathological process in animal models of PD. Understanding the relationship between α-syn and subsequent inflammation may reveal novel targets for neuroprotective interventions. In this review, we examine the role of α-syn and modified forms of this protein in the initiation of innate and adaptive immune responses.

Topics: Adaptive Immunity; alpha-Synuclein; Humans; Immunity, Innate; Parkinson Disease

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder with severe consequences for patients and caregivers. In the last twenty years of research, alpha-synuclein (αSyn) emerged as a main regulator of PD pathology, both in genetic and sporadic cases. Most importantly, oligomeric and aggregated species of αSyn appear to be pathogenic. In addition, transition metals have been implicated in the disease pathogenesis of PD already for decades. The interaction of metals with αSyn has been shown to trigger the aggregation of this protein. Furthermore, metals can exert cellular toxicity due to their red-ox potential, which leads to the formation of reactive oxygen species, exacerbating the noxious effects of αSyn. Here we give a brief overview on αSyn pathology and the role of metals in the brain and then address in more detail the interaction of αSyn with three disease-relevant transition metals, iron (Fe), copper (Cu) and manganese (Mn). We also discuss possible therapeutic approaches for PD, which are based on these interactions, e.g. chelation therapy and anti-oxidative treatments. Not all mechanisms of alpha-synuclein-mediated toxicity and roles of metals are sufficiently understood. We discuss several aspects, which deserve further investigation in order to shed light on the etiopathology of the disease and enable the development of more specific, innovative drugs for the treatment of PD and other synucleinopathies.

Topics: alpha-Synuclein; Biological Transport; Brain; Humans; Metals; Models, Biological; Parkinson Disease

It has been reported that single nucleotide polymorphisms (SNPs) of Alpha-synuclein (SNCA) are associated with Parkinson's disease (PD). Some researchers have attempted to validate this finding in various ethnic populations. The results of studies concerning SNCA polymorphisms and PD susceptibility remain conflicting. To evaluate the association between these SNPs and PD, the authors conducted a series of meta-analyses using a predefined protocol. Databases including PubMed, MEDLINE and PD gene were searched to identify relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. All analyses were calculated using STATA11.0. A total of 19 studies on the SNPS rs181489, rs356186, rs356219, rs894278, rs2583988, rs2619363, rs2619364, rs2737029, rs10005233 and rs11931074 were included. This meta-analysis showed that eight out of these 10 candidate SNPs may be associated with PD risk. Significant association was found between PD and the following SNPs: rs181489, rs356186, rs356219, rs894278 rs2583988, rs2619364, rs10005233 and rs11931074. Among these SNPs, rs356186 was found to be the only SNP that may play a protective role in Parkinson's disease. These results suggest that the SNCA gene may be associated with PD.

Topics: alpha-Synuclein; Genetic Predisposition to Disease; Humans; Parkinson Disease; Polymorphism, Single Nucleotide; Publication Bias; Risk Factors

Recent research suggests a complex role for microglia not only in Parkinson's disease but in other disorders involving alpha-synuclein aggregation, such as multiple system atrophy. In these neurodegenerative processes, the activation of microglia is a common pathological finding, which disturbs the homeostasis of the neuronal environment otherwise maintained, among others, by microglia. The term activation comprises any deviation from what otherwise is considered normal microglia status, including cellular abundance, morphology or protein expression. The microglial response during disease will sustain survival or otherwise promote cell degeneration. The novel concepts of alpha-synuclein being released and uptaken by neighboring cells, and their importance in disease progression, positions microglia as the main cell that can clear and handle alpha-synuclein efficiently. Microglia's behavior will therefore be a determinant on the disease's progression. For this reason we believe that the better understanding of microglia's response to alpha-synuclein pathological accumulation across brain areas and disease stages is essential to develop novel therapeutic tools for Parkinson's disease and other alpha-synucleinopathies. In this review we will revise the most recent findings and developments with regard to alpha-synuclein and microglia in Parkinson's disease.

Topics: alpha-Synuclein; Animals; Brain; Gene Expression Regulation; Humans; Interleukin-1beta; Microglia; Parkinson Disease; Tumor Necrosis Factor-alpha

Classically defined phenotypically by a triad of cerebellar ataxia, parkinsonism, and autonomic dysfunction in conjunction with pyramidal signs, multiple system atrophy (MSA) is a rare and progressive neurodegenerative disease affecting an estimated 3-4 per every 100,000 individuals among adults 50-99 years of age. With a pathological hallmark of alpha-synuclein-immunoreactive glial cytoplasmic inclusions (GCIs; Papp-Lantos inclusions), MSA patients exhibit marked neurodegenerative changes in the striatonigral and/or olivopontocerebellar structures of the brain. As a member of the alpha-synucleinopathy family, which is defined by its well-demarcated alpha-synuclein-immunoreactive inclusions and aggregation, MSA's clinical presentation exhibits several overlapping features with other members including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Given the extensive fund of knowledge regarding the genetic etiology of PD revealed within the past several years, a genetic investigation of MSA is warranted. While a current genome-wide association study is underway for MSA to further clarify the role of associated genetic loci and single-nucleotide polymorphisms, several cases have presented solid preliminary evidence of a genetic etiology. Naturally, genes and variants manifesting known associations with PD (and other phenotypically similar neurodegenerative disorders), including SNCA and MAPT, have been comprehensively investigated in MSA patient cohorts. More recently variants in COQ2 have been linked to MSA in the Japanese population although this finding awaits replication. Nonetheless, significant positive associations with subsequent independent replication studies have been scarce. With very limited information regarding genetic mutations or alterations in gene dosage as a cause of MSA, the search for novel risk genes, which may be in the form of common variants or rare variants, is the logical nexus for MSA research. We believe that the application of next generation genetic methods to MSA will provide valuable insight into the underlying causes of this disease, and will be central to the identification of etiologic-based therapies.

Topics: Alkyl and Aryl Transferases; alpha-Synuclein; Animals; Disease Models, Animal; Genetic Linkage; Genome-Wide Association Study; Humans; Lewy Body Disease; Multiple System Atrophy; Mutation; Parkinson Disease

Parkinson's disease is primarily a movement disorder with predilection for the nigral dopaminergic neurons and is often associated with widespread neurodegeneration and diffuse Lewy body deposition. Recent advances in molecular genetics and studies in model organisms have transformed our understanding of Parkinson's pathogenesis and suggested unifying biochemical pathways despite the clinical heterogeneity of the disease. In this review, we summarized the evidence that a number of Parkinson's associated genetic mutations or polymorphisms (LRRK2, VPS35, GBA, ATP13A2, ATP6AP2, DNAJC13/RME-8, RAB7L1, GAK) disrupt protein trafficking and degradation via the endosomal pathway and discussed how such defects could arise from or contribute to the accumulation and misfolding of α-synuclein in Lewy bodies. We propose that an age-related pathological depletion of functional endolysosomes due to neuromelanin deposition in dopaminergic neurons may increase their susceptibility to stochastic molecular defects in this pathway and we discuss how enzymes that regulate ubiquitin signaling, as exemplified by the ubiquitin ligase Nedd4, could provide the missing link between genetic and acquired defects in endosomal trafficking. This article is part of a Special Issue entitled 'Neuronal Protein'.

Topics: alpha-Synuclein; Animals; Dopaminergic Neurons; Endosomes; Humans; Melanins; Mutation; Parkinson Disease; Protein Transport; Signal Transduction

Parkinson's disease is an incurable neurodegenerative disease. Most cases of the disease are of sporadic origin, but about 10% of the cases are familial. The genes thus far identified in Parkinson's disease are well conserved. Drosophila is ideally suited to study the molecular neuronal cell biology of these genes and the pathogenic mutations in Parkinson's disease. Flies reproduce quickly, and their elaborate genetic tools in combination with their small size allow researchers to analyze identified cells and neurons in large numbers of animals. Furthermore, fruit flies recapitulate many of the cellular and molecular defects also seen in patients, and these defects often result in clear locomotor and behavioral phenotypes, facilitating genetic modifier screens. Hence, Drosophila has played a prominent role in Parkinson's disease research and has provided invaluable insight into the molecular mechanisms of this disease.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Drosophila; Drosophila Proteins; Humans; Parkinson Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by the preferential loss of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction is increasingly appreciated as a key determinant of dopaminergic neuronal susceptibility in PD and is a feature of both familial and sporadic disease, as well as in toxin-induced Parkinsonism. Recently, the mechanisms by which PD-associated mitochondrial proteins phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1 (PINK1) and parkin function and induce neurodegeneration have been identified. In addition, increasing evidence implicates other PD-associated proteins such as α-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) in mitochondrial dysfunction in genetic cases of PD with the potential for a large functional overlap with sporadic disease. This review highlights how recent advances in understanding familial PD-associated proteins have identified novel mechanisms and therapeutic strategies for addressing mitochondrial dysfunction in PD.

Topics: alpha-Synuclein; Animals; Humans; Mitochondria; Parkinson Disease

Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyotrophic Lateral Sclerosis; Animals; Autophagy; DNA-Binding Proteins; Humans; Huntingtin Protein; Huntington Disease; Lysosomes; Molecular Targeted Therapy; Mutation; Nerve Tissue Proteins; Neurodegenerative Diseases; Parkinson Disease; Prion Diseases; Proteasome Endopeptidase Complex; Proteolysis; Proteostasis Deficiencies; PrPSc Proteins; Superoxide Dismutase; tau Proteins; Ubiquitin

Mutations of the glucocerebrosidase (GBA) gene are the most important risk factor yet discovered for Parkinson disease (PD). Homozygous GBA mutations result in Gaucher disease (GD), a lysosomal storage disorder. Heterozygous mutations have not until recently been thought to be associated with any pathological process. However, it is clear that the presence of a GBA mutation in homozygous or heterozygous form is associated with an approximately 20-fold increase in the risk for PD, with little if any difference in risk burden related to gene dose. Most studies suggest that 5-10% of PD patients have GBA mutations, although this figure is greater in the Ashkenazi population and may be an underestimate overall if the entire exome is not sequenced. GBA-associated PD is clinically indistinguishable from idiopathic PD, except for slightly earlier age of onset and a greater frequency of cognitive impairment. Pathological and imaging features, and response to pharmacotherapy are identical to idiopathic PD. GBA mutations result in reduced enzyme activity and mutant protein may become trapped in the endoplasmic reticulum (ER) leading to unfolded protein response and ER associated degradation and stress. Both mechanisms may be relevant in GD and PD pathogenesis and lead to impaired lysosomal function. Of particular relevance to PD is the interaction of glucocerebrosidase enzyme (GCase) with alpha-synuclein (SNCA). There appears to be a bi-directional reciprocal relationship between GCase levels and those of SNCA. Thus reduced GCase in GBA mutation PD brain is associated with increased SNCA, and increased SNCA deposition is associated with reduced GCase even in GBA wild-type PD brains. It is noteworthy that GBA mutations are also associated with an increase in risk for dementia with Lewy bodies, another synucleinopathy. It has been suggested that the relationship between GCase and SNCA may be leveraged to reduce SNCA levels in PD by enhancing GCase levels and activity. This hypothesis has been confirmed in GBA mutant mice, PD patient fibroblasts and cells with SNCA overexpression, and offers an important target pathway for future neuroprotection therapy in PD. This article is part of a Special Issue entitled 'Neuronal Protein'.

Topics: alpha-Synuclein; Animals; Glucosylceramidase; Humans; Lysosomes; Mutation; Parkinson Disease

The etiology and pathogenesis of neurodegenerative disorders has yet to be elucidated, so their differential diagnosis is a challenge. This is especially true in differentiating Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson disease (PD), and multiple system atrophy (MSA).. A total of 11 eligible articles were identified by search of electronic databases including PubMed, Springer Link, Elsevier, and the Cochrane Library, up to June 2014. In meta-analyses, standardized mean differences (SMD), with 95% confidence intervals (CI), comparing cerebrospinal fluid (CSF) measures of α-synuclein between the above conditions were calculated using random-effects models.. CSF α-synuclein concentrations were significantly higher in AD compared to DLB [SMD: 0.32, 95% CI: (0.02, 0.62), z = 2.07, P = 0.038]; PD [SMD: 0.87, 95% CI: (0.15, 1.58), z = 2.38, P = 0.017]; or MSA [SMD: 1.14, 95% CI: (0.15, 2.14), z = 2.25, P = 0.025]. However, no significant difference was found between patients with AD and neurological cognitively normal controls [SMD: 0.02, 95% CI: (-0.21, 0.24), z = 0.13, P = 0.894].. Results of these meta-analysis suggest that quantification of CSF α-synuclein could help distinguish AD from other neurodegenerative disorders such as DLB, PD, or MSA.

Topics: alpha-Synuclein; Alzheimer Disease; Diagnosis, Differential; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

Parkinson's disease is the second most common neurodegenerative disease which affects almost 1 percent of the population above the age of 60. It is is characterized by loss of dopaminergic neurons in the striatum and substantia nigra, coupled with the formation of intracellular Lewy bodies in degenerating neurons. Recent evidence suggests endoplasmic reticulum stress as a common and prominent occurrence in the progression of Parkinson's disease pathogenesis in the affected human brain. One of the cellular defense mechanism to combat endoplasmic reticulum stress due to excessive protein accumulation is through activation of the unfolded protein response pathway. In this review we focus on the impact and role of this unfolded protein response as a causative factor of Parkinson's disease leading to neurodegeneration.

Topics: alpha-Synuclein; Animals; Brain; Humans; Neurodegenerative Diseases; Parkinson Disease; Unfolded Protein Response

Parkinson's disease (PD), a progressive neurodegenerative disease primarily affecting voluntary and controlled movement, is characterized by abnormal accumulations of α-synuclein (α-syn) in intraneuronal Lewy bodies. In the last years, the increased number of evidences from both the in vitro and in vivo studies has shown the ability of α-syn to misfold in amyloid conformations and to spread via neuron-to-neuron transmission, suggesting a prion-like behaviour. However, in contrast to prion protein (PrP), α-syn transmission is far from neuronal invasion. The high neuronal toxicity of both mature fibres and oligomeric species, as well as the intracellular localization of the protein and the difficulty to be secreted, could be key factors impeding the prion ability of α-syn aggregates.

Topics: alpha-Synuclein; Amyloid; Animals; Humans; Lewy Bodies; Parkinson Disease; Protein Folding

Parkinson's Disease (PD) is a complex neurodegenerative disorder classically characterized by movement impairment. Pathologically, the most striking features of PD are the loss of dopaminergic neurons and the presence of intraneuronal protein inclusions primarily composed of alpha-synuclein (α-syn) that are known as Lewy bodies and Lewy neurites in surviving neurons. Though the mechanisms underlying the progression of PD pathology are unclear, accumulating evidence suggests a prion-like spreading of α-syn pathology. The intracellular homeostasis of α-syn requires the proper degradation of the protein by three mechanisms: chaperone-mediated autophagy, macroautophagy and ubiquitin-proteasome. Impairment of these pathways might drive the system towards an alternative clearance mechanism that could involve its release from the cell. This increased release to the extracellular space could be the basis for α-syn propagation to different brain areas and, ultimately, for the spreading of pathology and disease progression. Here, we review the interplay between α-syn degradation pathways and its intercellular spreading. The understanding of this interplay is indispensable for obtaining a better knowledge of the molecular basis of PD and, consequently, for the design of novel avenues for therapeutic intervention.

Topics: alpha-Synuclein; Animals; Autophagy; Humans; Parkinson Disease; Proteolysis

Parkinson's Disease (PD) and alpha synucleinopathies are multifactorial disorders, which manifest through motor symptoms and non-motor symptoms involving the Central Nervous System (CNS), the Peripheral Nervous System (PNS) and, recently, also the Enteric Nervous System (ENS). The typical hallmarks of alpha synucleinopathies are proteinaceous inclusions of alpha synuclein (αS). In PD they are known as Lewy Bodies (LBs) and Lewy Neurites (LNs), discovered in dopaminergic neurons of substantia nigra (pars compacta) as well as in other regions of the central and peripheral nervous systems. Despite the clear causes which lead to LBs/LNs are still unknown, according to Braak's theory, these inclusions appear first in PNS to spread, following neuronal innervation, towards the CNS in a spatio- temporal dissemination described in a staging procedure. In line with these observations, several animal models have been used with the purpose to reproduce PD as well as to propose new therapeutic approaches. Different pathways can cooperate to neurodegeneration in PD such as genetic mutations of αS gene, mitochondrial dysfunctions, neuroinflammation. The present review highlights αS as the key-word for PD pathology and alpha synucleinopathies and a main target in PD research. Several therapeutic approaches can be proposed, however all of them are addressed in advanced stages of the pathology. Our focus will be the alteration of αS physiological pathway, which allows to address therapy in early stages at intracellular or extracellular level, such as the use of anti ER-stress compounds and innovative immunotherapy, which could be promising tools to reduce neuronal degeneration and to halt PD progression.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Biomarkers; Disease Progression; Dopaminergic Neurons; Early Diagnosis; Gastrointestinal Diseases; Humans; Immunotherapy; Lewy Bodies; Lewy Body Disease; Mice; Mice, Transgenic; Mitochondria; Models, Neurological; Molecular Targeted Therapy; Neuroglia; Organ Specificity; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Protein Structure, Tertiary; Rats; Single-Chain Antibodies; Unfolded Protein Response; Vagus Nerve

The importance of ATP13A2 (PARK9) in Parkinson's disease (PD) has emerged with the discovery that mutations in this gene cause Kufor-Rakeb syndrome, an autosomal recessive, juvenile-onset form of parkinsonism associated with the additional clinical triad of spasticity, supranuclear gaze palsy, and dementia. Eleven independent kindreds with homozygous or compound heterozygous ATP13A2 mutations have been identified. These reports make it clear that the condition exhibits considerable clinical heterogeneity, with a spectrum of disease even among family members carrying the same mutation. The relevance of the protein in sporadic PD is demonstrated by the presence of single heterozygous ATP13A2 mutations in this group of patients and altered expression of the gene in the substantia nigra from patients with the disease. The involvement of ATP13A2 in Zn(2+) homeostasis has recently been demonstrated, with the molecular consequences of this disturbance causing lysosomal impairment, α-synuclein accumulation, and mitochondrial dysfunction. These discoveries provide a new understanding of the role that ATP13A2 plays in the development of PD and identify a therapeutic target that may ameliorate α-synuclein accumulation and lysosomal and mitochondrial dysfunction in Parkinson's disease. © 2015 International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Heterozygote; Homeostasis; Humans; Lysosomes; Mitochondria; Mutation; Parkinson Disease; Phenotype; Proton-Translocating ATPases; Substantia Nigra; Zinc

The budding yeast Saccharomyces cerevisiae represents an established model system to study the molecular mechanisms associated to neurodegenerative disorders. A key-feature of Parkinson's disease is the formation of Lewy bodies, which are cytoplasmic protein inclusions. Misfolded α-synuclein is one of their main constituents. Expression of α-synuclein protein in yeast leads to protein aggregation and cellular toxicity, which is reminiscent to Lewy body containing human cells. The molecular mechanism involved in clearance of α-synuclein aggregates is a central question for elucidating the α-synuclein-related toxicity. Cellular clearance mechanisms include ubiquitin mediated 26S proteasome function as well as lysosome/vacuole associated degradative pathways as autophagy. Various modifications change α-synuclein posttranslationally and alter its inclusion formation, cytotoxicity and the distribution to different clearance pathways. Several of these modification sites are conserved from yeast to human. In this review, we summarize recent findings on the effect of phosphorylation and sumoylation of α-synuclein to the enhanced channeling to either the autophagy or the proteasome degradation pathway in yeast model of Parkinson's disease.

Topics: alpha-Synuclein; Humans; Parkinson Disease; Protein Aggregates; Protein Processing, Post-Translational; Saccharomyces cerevisiae; Sumoylation

Familial cases of Parkinson's disease (PD) can be associated with overexpression or mutation of α-synuclein, a synaptic protein reported to be localized mainly in the cytosol and mitochondria. We recently showed that wild-type α-synuclein is not present in mitochondria, as previously thought, but rather is located in mitochondrial-associated endoplasmic reticulum membranes. Remarkably, we also found that PD-related mutated α-synuclein results in its reduced association with mitochondria-associated membranes, coincident with a lower degree of apposition of endoplasmic reticulum with mitochondria and an increase in mitochondrial fragmentation, as compared with wild-type. This new subcellular localization of α-synuclein raises fundamental questions regarding the relationship of α-synuclein to mitochondria-associated membranes function, in both normal and pathological states. In this article, we attempt to relate aspects of PD pathogenesis to what is known about mitochondria-associated membranes' behavior and function. We hypothesize that early events occurring in dopaminergic neurons at the level of the mitochondria-associated membranes could cause long-term disturbances that lead to PD.

Topics: alpha-Synuclein; Endoplasmic Reticulum; Humans; Intracellular Membranes; Mitochondria; Parkinson Disease

Alternative splicing is a crucial mechanism of gene expression regulation that enormously increases the coding potential of our genome and represents an intermediate step between messenger RNA (mRNA) transcription and protein posttranslational modifications. Alternative splicing occupies a central position in the development and functions of the nervous system. Therefore, its deregulation frequently leads to several neurological human disorders. In the present review, we provide an updated overview on the impact of alternative splicing in Parkinson's disease (PD), the second most common neurodegenerative disorder worldwide. We will describe the alternative splicing of major PD-linked genes by collecting the current evidences about this intricate and not carefully explored aspect. Assessing the role of this mechanism on PD pathobiology may represent a central step toward an improved understanding of this complex disease.

Topics: alpha-Synuclein; Alternative Splicing; Animals; Brain; Humans; Intracellular Signaling Peptides and Proteins; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Oncogene Proteins; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Protein Serine-Threonine Kinases; RNA, Messenger; Ubiquitin-Protein Ligases; Vesicular Transport Proteins

Mutations and duplication/triplication of the alpha-synuclein (αSyn)-coding gene have been found to cause familial Parkinson's disease (PD), while genetic polymorphisms in the region controlling the expression level and stability of αSyn have been identified as risk factors for idiopathic PD, pointing to the importance of wild-type (wt) αSyn dosage in the disease. Evidence that αSyn is present in the cerebrospinal fluid and interstitial brain tissue and that healthy neuronal grafts transplanted into PD patients often degenerate suggests that extracellularly-released αSyn plays a role in triggering the neurodegenerative process. αSyn's role in neurotransmission has been shown in various cell culture models in which the protein was upregulated or deleted and in knock out and transgenic animal, with different results on αSyn's effect on synaptic vesicle pool size and mobilization, αSyn being proposed as a negative or positive regulator of neurotransmitter release. In this review, we discuss the effect of αSyn on pre- and post-synaptic compartments in terms of synaptic vesicle trafficking, calcium entry and channel activity, and we focus on the process of exocytosis and internalization of αSyn and on the spreading of αSyn-driven effects due to the presence of the protein in the extracellular milieu.

Topics: alpha-Synuclein; Animals; Exocytosis; Humans; Parkinson Disease; Synaptic Transmission

Axonal swellings are histological hallmarks of axonopathies in various types of disorders in the central nervous system, including neurodegenerative diseases. Given the pivotal role of axonopathies during the early phase of neurodegenerative process, axonal swellings may be good models which may provide some clues for early pathogenesis of α-synucleinopathies, including Parkinson's disease and dementia with Lewy bodies (DLB). In this mini-review, such a possibility is discussed based on our recent studies as well as other accumulating studies. Consistent with the current view that dysfunction in the autophagy-lysosomal system may play a major role in the formation of axonal swellings, our studies showed globule, small axonal swellings, derived from transgenic mice expressing either human wild-type α-synuclein (αS-globule) or DLB-linked P123H β-synuclein (βS-globule), contained autophagosome-like membranes. However, other pathological features, such as abnormal mitochondria, enhanced oxidative stress and LRRK2 accumulation, were observed in the αS-globules, but not in the βS-globules. Collectively, it is predicted that αS and βS may be involved in axonopathies through similar but distinct mechanisms, and thus, contribute to diverse axonal pathologies. Further studies of the axonal swellings may lead to elucidating the pathogenic mechanism of early α-synucleinopathies and illuminating a strategy for a disease-modifying therapy against these devastating disorders.

Topics: alpha-Synuclein; Animals; Autophagy; Axons; beta-Synuclein; Humans; Lewy Bodies; Parkinson Disease

Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes α-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinson's disease has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of α-synuclein in the pathogenesis of Parkinson's disease has led researchers to consider the therapeutic potential of several strategies aimed at reduction of α-synuclein toxicity. We critically assess the potential of experimental therapies targeting α-synuclein, and discuss steps that need to be taken for target validation and drug development.

Topics: alpha-Synuclein; Animals; Drug Discovery; Humans; Parkinson Disease

Parkinson's disease (PD) is a very common neurodegenerative disorder characterized by the accumulation of α-synuclein (α-syn) into Lewy body (LB) inclusions and the loss of neuronmelanin (NM) containing dopamine (DA) neurons in the substantia nigra (SN). Pathological α-syn and NM are two prominent hallmarks in this selective and progressive neurodegenerative disease. Pathological α-syn can induce dopaminergic neuron death by various mechanisms, such as inducing oxidative stress and inhibiting protein degradation systems. Therefore, to explore the factors that trigger α-syn to convert from a non-toxic protein to toxic one is a pivotal question to clarify the mechanisms of PD pathogenesis. Many triggers for pathological α-syn aggregation have been identified, including missense mutations in the α-syn gene, higher concentration, and posttranslational modifications of α-Syn. Recently, the role of NM in inducing α-syn expression and aggregation has been suggested as a mechanism for this pigment to modulate neuronal vulnerability in PD. NM may be responsible for PD and age-associated increase and aggregation in α-syn. Here, we reviewed our previous study and other recent findings in the area of interaction between NM and α-syn.

Topics: alpha-Synuclein; Animals; Humans; Melanins; Oxidative Stress; Parkinson Disease; Protein Aggregation, Pathological

Parkinson's disease (PD) is the second most common neurodegenerative disease, and the most prevalent degenerative movement disorder. It is estimated that the prevalence of such age-related neurodegenerative diseases will double in the next 25 years. While the etiology of Parkinson's disease is not entirely clear, a common link between both inherited and sporadic forms of disease is the protein α-synuclein. In PD brains, α-synuclein is typically found in large, insoluble protein aggregates referred to as Lewy bodies and Lewy neurites. The exact role of α-synuclein is still unknown, but it has been shown to undergo a variety of post-translational modifications, which impact α-synuclein aggregation and oligomer formation in different ways. This review highlights key post-translational modifications and the impact they have on α-synuclein aggregation and toxicity, elucidating potential mechanisms for PD pathogenesis and targets for future therapeutics. This article is part of a Special Issue entitled SI: Neuroprotection.

Topics: alpha-Synuclein; Animals; Brain; Humans; Parkinson Disease; Protein Processing, Post-Translational

Parkinson's disease (PD) is a common motor neurodegenerative disorder with multifactorial etiology that is an increasing burden on our aging society. PD is characterized by nigrostriatal degeneration which might involve oxidative stress, α-synuclein (αS) aggregation, dysregulation of redox metal homeostasis and neurotoxicity. Although the exact cause remains unknown, both genetic and environmental factors have been implicated. Among the various environmental factors tea consumption has attracted increasing interest, as besides being one of the most consumed beverages in the world, tea contains specific polyphenols which can play an important role in delaying the onset or halting the progression of PD. Green and black teas are rich sources of polyphenols, the most abundant being epigallocatechin-3-gallate (EGCG) and theaflavins. There is now consistent mechanistic data on the neuroprotective and neuroregenerative effects of tea polyphenols, indicating that they do not just possess anti-oxidant or anti-chelating properties but may directly interfere with aggregation of the αS protein and modulate intracellular signalling pathways, both in vitro and in animal models. EGCG in green tea has been by far the most studied compound and therefore future investigations should address more the effects of other polyphenols, especially theaflavins in black tea. Nevertheless, despite significant data on their potential neuroprotective effects, clinical studies are still very limited and to date only EGCG has reached phase II trials. This review collates the current knowledge of tea polyphenols and puts into perspective their potential to be considered as nutraceuticals that target various pathologies in PD.

Topics: alpha-Synuclein; Antioxidants; Biflavonoids; Catechin; Humans; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Polyphenols; Tea

In the past few years, there have been a large number of genes identified that contribute to the lifetime risk of Parkinson's disease (PD). Some genes follow a Mendelian inheritance pattern, but others are risk factors for apparently sporadic PD. Here, we will focus on those genes nominated by genome-wide association studies (GWAS) in sporadic PD, with a particular emphasis on genes that overlap between familial and sporadic disease such as those encoding a-synuclein (SNCA), tau (MAPT), and leucine-rich repeat kinase 2 (LRRK2). We will advance the view that there are likely relationships between these genes that map not only to neuronal processes, but also to neuroinflammation. We will particularly discuss evidence for a role of PD proteins in microglial activation and regulation of the autophagy-lysosome system that is dependent on microtubule transport in neurons. Thus, there are at least two non-mutually exclusive pathways that include both non-cell-autonomous and cell-autonomous mechanisms in the PD brain. Collectively, these data have highlighted the amount of progress made in understanding PD and suggest ways forward to further dissect this disorder.

Topics: alpha-Synuclein; Animals; Autonomic Pathways; Genome-Wide Association Study; Humans; Inflammation; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Metabolic Networks and Pathways; Parkinson Disease; Parkinsonian Disorders; Protein Serine-Threonine Kinases; tau Proteins

Cognitive impairment may appear at the earliest stages in Parkinson's disease (PD). To assess the prevalence of mild cognitive impairment (MCI) and its different subtypes, as transitional stage, is complicated by the lack of consensus diagnostic criteria.. To review MCI in PD (MCI-PD), diagnostic criteria and predictive factors of conversion to dementia.. Systematic review of articles published in Medline (PubMed) using the combination of keywords 'mild cognitive impairment' and 'Parkinson's disease'.. MCI-PD diagnostic criteria published by the Movement Disorders Society are an interesting tool for the diagnosis, in spite they are not validated. Its implementation has the following limitations: 1) the heterogeneity of cognitive deficits described in PD; 2) a variable evolution of cognitive symptoms in PD which difficult the identification of dementia predictors; 3) selection of the more appropriate neuropsychological tests and cut-off points; 4) patient characteristics, disease stage and type of antiparkinsonian treatment.. Neuropsychological subtypes, neuroimaging, biomarkers or limitation in some instrumental activities seem to be very sensitive for detecting patients with MCI-PD and increased risk of conversion to dementia.. Subtipos de deterioro cognitivo leve en la enfermedad de Parkinson y factores predictores de conversion a demencia.. Introduccion. El deterioro cognitivo puede aparecer en las etapas mas iniciales de la enfermedad de Parkinson (EP). Determinar la prevalencia del deterioro cognitivo leve (DCL) como etapa de transicion o sus diferentes perfiles resulta complicado por la ausencia de criterios diagnosticos consensuados. Objetivo. Revisar el concepto de DCL en la EP, sus criterios diagnosticos y los factores predictores de conversion a demencia. Pacientes y metodos. Revision sistematica de los articulos publicados en Medline (PubMed) utilizando la combinacion de las palabras clave 'deterioro cognitivo leve' y 'enfermedad de Parkinson'. Resultados. Los criterios diagnosticos del DCL en la EP publicados por la Sociedad de Trastornos del Movimiento, a pesar de no estar validados, constituyen una importante herramienta para el diagnostico de estos pacientes. Su aplicacion se ve influida por las siguientes limitaciones: la heterogeneidad de los deficits cognitivos descritos en la EP, su evolucion variable, que dificulta el hallazgo de factores predictores de conversion a demencia, la seleccion de las pruebas neuropsicologicas mas apropiadas y la determinacion de los puntos de corte mas idoneos, y las caracteristicas del paciente, etapa de la enfermedad y tipo de tratamiento antiparkinsoniano. Conclusiones. Marcadores neuropsicologicos, de neuroimagen, biomarcadores o la limitacion en algunas actividades instrumentales son muy prometedores para la deteccion de pacientes con DCL en la EP y riesgo elevado de conversion a demencia.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Atrophy; Attention; Biomarkers; Brain; Cognitive Dysfunction; Cross-Sectional Studies; Dementia; Disease Progression; Executive Function; Humans; Language Disorders; Longitudinal Studies; Memory Disorders; Neuroimaging; Neuropsychological Tests; Parkinson Disease; Peptide Fragments; Prevalence; Quality of Life; Research Design; Risk Factors; Severity of Illness Index; Symptom Assessment

The role of protein aggregates, such as Lewy body inclusions, in the molecular pathogenesis of Parkinson's disease has remained controversial and elusive. The protein α-synuclein is a major component of these inclusions but it can exist in many alternate conformations. Here we review advances in our understanding of the roles of Lewy pathology and α-synuclein in Parkinson's disease.. Recent work has demonstrated that certain α-synuclein conformations are directly toxic to neurons and may also propagate Lewy pathology within the nervous system. Investigation into clinicopathological correlates in rare genetic forms of Parkinson's disease has revealed that Lewy pathology is associated with nonmotor features but may not contribute to motor symptoms in Parkinson's disease.. These recent findings open up new avenues of investigation into the molecular pathogenesis of Parkinson's disease. Future work will need to identify the most toxic conformations of α-synuclein and define their relationship to Lewy pathology. This work will be necessary to be able to develop novel therapeutic strategies that target specific pathogenic forms of α-synuclein for disease modification in Parkinson's disease.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Neurons; Parkinson Disease

Parkinson's disease (PD) is cited to be the second most common neuronal degenerative disorders; however, the exact mechanism of PD is still unclear. α-synuclein is one of the key proteins in PD pathogenesis as it's the main component of the PD hallmark Lewy bodies (LBs). Nowadays, the study of α-synuclein phosphorylation mechanism related to the PD pathology has become a research hotspot, given that 90% of α-synuclein deposition in LBs is phosphorylated at Ser129, whereas in normal brains, only 4% or less of α-synuclein is phosphorylated at the residue. Here, we review the related study of PD pathological mechanism involving the phosphorylation of α-synuclein mainly at Ser129, Ser87, and Tyr125 residues in recent years, as well as some explorations relating to potential clinical application, in an attempt to describe the development and implication for the mechanism and therapy of PD. Given that some of the studies have yielded paradoxical results, there is need for more comprehensive research in the field. The phosphorylation of α-synuclein might provide a breakthrough for PD mechanism study and even supply a new therapeutic strategy. The milestone study on the phosphorylation of α-synuclein mainly at Ser129, Ser87, and Tyr125 relating to PD in recent years as well as some clinical application exploration are overviewed. The potential pathways of the phosphorylated α-synuclein related to PD are also summarized. The review may supply more ideas and thinking on this issue for the scientists in related research field.

Topics: alpha-Synuclein; Animals; Brain; Humans; Nerve Tissue Proteins; Neurons; Parkinson Disease; Phosphorylation

There is still an open debate whether multiple sclerosis (MS) lesions can cause parkinsonian symptoms, or the coexistence of both diseases in the same patient is accidental. Moreover, α-synuclein (α Syn), the hallmark of Parkinson's disease (PD) seems also to play a crucial role in MS. So far, 42 cases of co-occurrence of parkinsonism and MS have been reported, but CSF α Syn measurement is lacking. To our knowledge, we report the first case with concomitant MS and PD diagnosis based on both clinico-radiological and CSF α Syn findings and review of literature.

Topics: alpha-Synuclein; Brain; Diagnosis, Differential; Female; Humans; Middle Aged; Multiple Sclerosis; Parkinson Disease; Parkinsonian Disorders; Treatment Outcome

α-Synuclein, a neuronal protein, plays a central role in the pathophysiology of Parkinson's disease (PD), the second most prevalent neurodegenerative disorder. Cases of PD have increased tremendously over the past decade necessitating the identification of new therapeutic targets to reduce patient morbidity and to improve PD patients' quality of life.. The purpose of this article is to provide an update on the role of α-synuclein in fibrils formation and review its role as an effective immunotherapeutic target for PD. The rapidly expanding evidence for the contribution of α-synuclein to the pathogenesis of PD led to the development of antibodies against the C terminus of α-synuclein and other molecules involved in the inflammatory signaling pathways that were found to contribute significantly to initiation and progression of the disease.. The readers will obtain new insights on the mechanisms by which α-synuclein can trigger the development of PD and other related degenerative disorders along with the potential role of active and passive antibodies targeted against specific form of α-synuclein aggregates to clear neurotoxicity, stop the propagation of the prion-like behavior of these oligomers and reverse neuronal degeneration associated with PD.

Topics: alpha-Synuclein; Animals; Disease Progression; Humans; Immunotherapy; Molecular Targeted Therapy; Parkinson Disease; Quality of Life; Signal Transduction

Currently, the pathophysiology of idiopathic Parkinson's disease is explained by a loss of mainly dopaminergic nerve cells that causes a neurotransmitter deficiency. In the final stage of the disease, there is a marked loss of neurons in the substantia nigra. In addition, Lewy bodies can be found in some of the remaining neurons, which serve as the pathological hallmark of the disease. These Lewy bodies are composed mainly of aggregated α-synuclein, a physiological presynaptic protein. Lewy bodies were thought to be the pathophysiologically relevant form of α-synuclein because their appearance coincided with neuron loss in the substantia nigra. In consequence, neuron loss was thought to be the primary step in the neurodegeneration in Parkinson's disease. On the other hand, the clinical syndrome suggests a synaptic disorder. If α-synuclein aggregation was causally linked to the pathophysiology of disease, α-synuclein pathology should be found at the synapse. As recently demonstrated, one to two orders of magnitude more α-synuclein aggregates are present in presynaptic terminals than in Lewy bodies or Lewy neurites. Degeneration of dendritic spines associated with synaptic α-synuclein aggregates has been shown to occur in human disease. In experiments, using transgenic mice or cell cultures, mild (two- to three-fold) overexpression of α-synuclein caused an altered vesicle turnover and led to a reduction in neurotransmitter release. Different approaches linked these alterations to presynaptic aggregation of α-synuclein. These findings may fundamentally change the pathophysiological concept of Parkinson's disease: not nerve cell loss, but the synaptic dysfunction of still existing nerve cells should become the focus of attention. From recent findings, it is quite evident that the death of dopaminergic neurons is a secondary event in the pathophysiology of Parkinson's disease.

Topics: alpha-Synuclein; Animals; Cell Death; Humans; Lewy Bodies; Neurons; Parkinson Disease; Synapses

Elevated levels of cholesterol and its metabolites (oxysterols) have been reported to be associated not only with several metabolic syndromes, but also become a prognostic risk factor of neurodegenerative diseases particularly Alzheimer's disease. The incidence and the prospect of Alzheimer's disease with respect to elevated levels of cholesterol have been studied extensively and reviewed earlier. Recently, several interesting findings have shown the occurrence of equivalent Parkinsonian pathologies in cellular neuronal models, mediated by oxysterols or excess exposure to cholesterol. In this regard, oxysterols are particular in causing alpha-synuclein aggregation and destruction of dopamine containing neurons in in vitro models, which is linked to their direct influence on oxidative stress provoking potency. Inspite of the significant in vitro reports, which suggest the relativeness of cholesterol or oxysterol towards Parkinsonism, several prospective clinical reports provided a negative or no correlation. However, few prospective clinical studies showed a positive correlation between plasma cholesterol and incidence of Parkinson's disease (PD). Also, few significant studies have convincingly demonstrated that high fat diet exacerbates parkinsonian pathologies, including loss of dopaminergic neurons and oxidative stress parameters in animal models of PD. The present review brings together all the neuropathological proceedings mediated by excess cholesterol or its metabolites in brain in the light of their contribution towards the onset of PD. Also we have reviewed the possibilities of cholesterol lowering efficacy of statin therapy, in reducing the occurrence of PD.

Topics: alpha-Synuclein; Animals; Brain; Cholesterol; Dopaminergic Neurons; Humans; Oxidative Stress; Parkinson Disease

The pathological assembly of Aβ, tau, and α-synuclein is at the heart of Alzheimer's and Parkinson's diseases. Extracellular deposits of Aβ and intraneuronal tau inclusions define Alzheimer's disease, whereas intracellular inclusions of α-synuclein make up the Lewy pathology of Parkinson's disease. Most cases of disease are sporadic, but some are inherited in a dominant manner. Mutations frequently occur in the genes encoding Aβ, tau, and α-synuclein. Overexpression of these mutant proteins can give rise to disease-associated phenotypes. Protein assembly begins in specific regions of the brain during the process of Alzheimer's and Parkinson's diseases, from where it spreads to other areas.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Brain; Humans; Lewy Bodies; Mutation; Parkinson Disease; Prion Diseases; Prion Proteins; Prions; tau Proteins

Parkinson's disease (PD) is an age-related progressive neurodegenerative disease associated with selective loss of dopaminergic neurons. The characteristic hallmark of the disease is intracytoplasmic proteinacious inclusion bodies called Lewy bodies, primarily consisting of a presynaptic protein α-synuclein. Oxidative stress-mediated damage to macromolecules have been shown to occur frequently in PD. Oxidative damage to DNA in the form of oxidized guanine (8-oxodG) accumulates in both the mitochondrial and nuclear DNA of dopaminergic neurons of the substantia nigra in PD. 8-oxodG-mediated transcriptional mutagenesis has been shown to have the potential to alter phenotype of cells through production of mutant pool of proteins. This review comprehensively summarizes the role of oxidative stress-mediated damage incurred during neurodegeneration, and highlights the scope of transcriptional mutagenesis event in leading to α-synuclein aggregation as seen in PD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; alpha-Synuclein; Amino Acid Sequence; Animals; Deoxyguanosine; Humans; Molecular Sequence Data; Mutagenesis; Oxidative Stress; Parkinson Disease; Protein Aggregation, Pathological; Substantia Nigra; Transcription, Genetic

The misfolding of α-synuclein is a critical event in the death of dopaminergic neurons and the progression of Parkinson's disease. Drugs that bind to α-synuclein and form a loop structure between the N- and C-terminus tend to be neuroprotective, whereas others that cause a more compact structure tend to be neurotoxic. The binding of several natural products and other drugs that are involved in dopamine metabolism were investigated by nanopore analysis and isothermal titration calorimetry. The antinausea drugs, cinnarizine and metoclopramide, do not bind to α-synuclein, whereas amphetamine and the herbicides, paraquat and rotenone, bind tightly and cause α-synuclein to adopt a more compact conformation. The recreational drug, cocaine, binds to α-synuclein, whereas heroin and methadone do not. Metformin, which is prescribed for diabetes and is neuroprotective, binds well without causing α-synuclein to adopt a more compact conformation. Methylphenidate (ritalin) binds to sites in both the N- and C-terminus and causes α-synuclein to adopt a loop conformation. In contrast, amphetamine only binds to the N-terminus. Except for cinnarizine and metoclopramide, there is a good correlation between the mode of binding to α-synuclein and whether a drug is neuroprotective or neurotoxic.

Topics: alpha-Synuclein; Animals; Humans; Molecular Conformation; Neuroprotective Agents; Neurotoxicity Syndromes; Parkinson Disease; Protein Binding

Currently, several α-synuclein immunotherapies are being tested in experimental Parkinson's disease models and in clinical trials. Recent research has revealed that α-synuclein is not just an intracellular synaptic protein but also exists extracellularly. Moreover, the transfer of misfolded α-synuclein between cells might be a crucial step in the process leading to a progressive increase in deposition of α-synuclein aggregates throughout the Parkinson's disease brain. The revelation that α-synuclein is present outside cells has increased the interest in antibody-based therapies and opens up for the notion that microglia might play a key role in retarding Parkinson's disease progression. The objectives of this review are to describe and contrast the use of active and passive immunotherapy in treating α-synucleinopathies and highlight the likely important role of microglia in clearing misfolded α-synuclein from the extracellular space.

Topics: alpha-Synuclein; Animals; Antibodies; Blood-Brain Barrier; Brain; Clinical Trials as Topic; Encephalitis; Humans; Immunotherapy; Microglia; Neurons; Parkinson Disease; Protein Aggregation, Pathological

α-Synuclein is an abundant neuronal protein which localizes predominantly to presynaptic terminals, and is strongly linked genetically and pathologically to Parkinson's disease and other neurodegenerative diseases. While the accumulation of α-synuclein in the form of misfolded oligomers and large aggregates defines multiple neurodegenerative diseases called "synucleinopathies", its cellular function has remained largely unclear, and is the subject of intense investigation. In this review, I focus on the structural characteristics of α-synuclein, its cellular and subcellular localization, and discuss how this relates to its function in neurons, in particular at the neuronal synapse.

Topics: alpha-Synuclein; Humans; Parkinson Disease; Synapses

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the preferential death of dopaminergic neurons. In the past two decades, great progress has been made toward understanding the pathogenesis of PD; however, its precise pathogenesis still remains unclear. Recently, accumulating evidence has suggested that macroautophagy (herein referred to as autophagy) is tightly linked to PD. Dysregulation of autophagic pathways has been observed in the brains of PD patients and in animal models of PD. More importantly, a number of PD-associated proteins, such as α-synuclein, LRRK2, Parkin and PINK1 have been further revealed to be involved in autophagy. Thus, it is now acknowledged that constitutive autophagy is essential for neuronal survival and that dysregulation of autophagy leads to PD. In this review, we focus on summarizing the relationships amongst PD-associated proteins, autophagy and PD. Moreover, we also demonstrate some autophagy-modulating compounds and autophagic microRNAs in PD models, which may provide better promising strategies for potential PD therapy.

Topics: alpha-Synuclein; Animals; Autophagy; Humans; Parkinson Disease

Parkinson's disease (PD) is characterized by alpha-synucleinopathy that affects all levels of the brain-gut axis including the central, autonomic, and enteric nervous systems. Recently, it has been recognized that the brain-gut axis interactions are significantly modulated by the gut microbiota via immunological, neuroendocrine, and direct neural mechanisms. Dysregulation of the brain-gut-microbiota axis in PD may be associated with gastrointestinal manifestations frequently preceding motor symptoms, as well as with the pathogenesis of PD itself, supporting the hypothesis that the pathological process is spread from the gut to the brain. Excessive stimulation of the innate immune system resulting from gut dysbiosis and/or small intestinal bacterial overgrowth and increased intestinal permeability may induce systemic inflammation, while activation of enteric neurons and enteric glial cells may contribute to the initiation of alpha-synuclein misfolding. Additionally, the adaptive immune system may be disturbed by bacterial proteins cross-reacting with human antigens. A better understanding of the brain-gut-microbiota axis interactions should bring a new insight in the pathophysiology of PD and permit an earlier diagnosis with a focus on peripheral biomarkers within the enteric nervous system. Novel therapeutic options aimed at modifying the gut microbiota composition and enhancing the intestinal epithelial barrier integrity in PD patients could influence the initial step of the following cascade of neurodegeneration in PD.

Topics: alpha-Synuclein; Animals; Biomarkers; Brain; Coffee; Diet; Enteric Nervous System; Gastrointestinal Microbiome; Gastrointestinal Tract; Helicobacter pylori; Humans; Immunity, Innate; Inflammation; Intestines; Mycobacterium tuberculosis; Parkinson Disease; Permeability; Protein Folding; Smoking

Ischemic heart disease (IHD) is the leading cause of death and disability worldwide. Therefore, novel therapeutic targets for protecting the heart against acute ischemia/reperfusion injury (IRI) are required to attenuate cardiomyocyte death, preserve myocardial function, and prevent the onset of heart failure. In this regard, a specific group of mitochondrial proteins, which have been linked to familial forms of Parkinson's disease (PD), may provide novel therapeutic targets for cardioprotection. In dopaminergic neurons of the substantia nigra, these PD proteins, which include Parkin, PINK1, DJ-1, LRRK2, and α-synuclein, play essential roles in preventing cell death-through maintaining normal mitochondrial function, protecting against oxidative stress, mediating mitophagy, and preventing apoptosis. These rare familial forms of PD may therefore provide important insights into the pathophysiology underlying mitochondrial dysfunction and the development of PD. Interestingly, these PD proteins are also present in the heart, but their role in myocardial health and disease is not clear. In this article, we review the role of these PD proteins in the heart and explore their potential as novel mitochondrial targets for cardioprotection.

Topics: alpha-Synuclein; Cardiotonic Agents; Cell Death; Humans; Intracellular Signaling Peptides and Proteins; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mitochondria; Mitophagy; Myocardial Ischemia; Myocardium; Myocytes, Cardiac; Oncogene Proteins; Oxidative Stress; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Protein Serine-Threonine Kinases; Reperfusion Injury; Ubiquitin-Protein Ligases

Accumulation of protein aggregates is the leading cause of cellular dysfunction in neurodegenerative disorders. Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, Prion disease and motor disorders such as amyotrophic lateral sclerosis, present with a similar pattern of progressive neuronal death, nervous system deterioration and cognitive impairment. The common characteristic is an unusual misfolding of proteins which is believed to cause protein deposition and trigger degenerative signals in the neurons. A similar clinical presentation seen in many neurodegenerative disorders suggests the possibility of shared neuronal responses in different disorders. Despite the difference in core elements of deposits in each neurodegenerative disorder, the cascade of neuronal reactions such as activation of glycogen synthase kinase-3 beta, mitogen-activated protein kinases, cell cycle re-entry and oxidative stress leading to a progressive neurodegeneration are surprisingly similar. This review focuses on protein toxicity in two neurodegenerative diseases, AD and PD. We reviewed the activated mechanisms of neurotoxicity in response to misfolded beta-amyloid and α-synuclein, two major toxic proteins in AD and PD, leading to neuronal apoptosis. The interaction between the proteins in producing an overlapping pathological pattern will be also discussed.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Humans; Parkinson Disease; Protein Folding; Signal Transduction

Parkinson's disease (PD) is associated with several non-motor symptoms, such as behavioral changes, urinary dysfunction, sleep disorders, fatigue and, above all, gastrointestinal (GI) dysfunction, including gastric dysmotility, constipation and anorectal dysfunction. Delayed gastric emptying, progressing to gastroparesis, is reported in up to 100% of patients with PD, and it occurs at all stages of the disease with severe consequences to the patient's quality of life. The presence of α-synuclein (α-syn) aggregates in myenteric neurons throughout the digestive tract, as well as morpho-functional alterations of the enteric nervous system (ENS), have been documented in PD. In particular, gastric dysmotility in PD has been associated with an impairment of the brain-gut axis, involving the efferent fibers of the vagal pathway projecting directly to the gastric myenteric plexus. The present review intends to provide an integrated overview of available knowledge on the possible role played by the ENS, considered as a semi-autonomous nervous network, in the pathophysiology of gastric dysmotility in PD. Particular attention has been paid review how translational evidence in humans and studies in pre-clinical models are allowing a better understanding of the functional, neurochemical and molecular alterations likely underlying gastric motor abnormalities occurring in PD.

Topics: alpha-Synuclein; Animals; Cholecystokinin; Efferent Pathways; Enteric Nervous System; Gastric Emptying; Gastrointestinal Motility; Gastroparesis; Humans; Mice; Mice, Transgenic; Models, Neurological; Neuromuscular Junction; Oxidopamine; Parkinson Disease; Parkinsonian Disorders; Protein Aggregates; Rats; Rotenone; Translational Research, Biomedical; Vagus Nerve

Accumulation and misfolding of the alpha-synuclein protein are core mechanisms in the pathogenesis of Parkinson's disease. While the normal function of alpha-synuclein is mainly related to the control of vesicular neurotransmission, its pathogenic effects are linked to various cellular functions, which include mitochondrial activity, as well as proteasome and autophagic degradation of proteins. Remarkably, these functions are also affected when the renewal of macromolecules and organelles becomes impaired during the normal aging process. As aging is considered a major risk factor for Parkinson's disease, it is critical to explore its molecular and cellular implications in the context of the alpha-synuclein pathology. Here, we discuss similarities and differences between normal brain aging and Parkinson's disease, with a particular emphasis on the nigral dopaminergic neurons, which appear to be selectively vulnerable to the combined effects of alpha-synuclein and aging.

Topics: Aging; alpha-Synuclein; Animals; Dopaminergic Neurons; Humans; Mitochondria; Parkinson Disease

Protein inclusions made up primarily of misfolded α-synuclein (α-Syn) are the hallmark of a set of disorders known as synucleinopathies, most notably Parkinson's disease (PD). It is becoming increasingly appreciated that α-Syn misfolding can spread to anatomically connected regions in a prion-like manner. The protein aggregates that ensue are correlated with neurodegeneration in the various yet select neuronal populations that are affected. Recent advances have begun to shed light on the spreading and toxicity mechanisms that may be occurring in PD. Several key emerging themes are arising from this work suggesting that α-Syn mediated neurodegeneration is due to a combination of relative α-Syn expression level, connectivity to affected brain regions, and intrinsic vulnerability to pathology.

Topics: alpha-Synuclein; Animals; Calcium; Dopaminergic Neurons; Humans; Oxidative Stress; Parkinson Disease; Protein Conformation; Protein Folding; Synaptic Transmission

Both iron and alpha-synuclein accumulation are one of hallmarks of Parkinson's disease (PD). Alpha-synuclein aggregation is often accompanied by abnormal accumulation of iron, indicating that there is a certain link between iron and alpha-synuclein aggregation. Iron promotes alpha-synuclein aggregation by increasing its synthesis and decreasing its degradation. Also, alpha-synuclein regulates iron metabolism through its ferrireductase activity. In this review, we will describe the roles of iron and alpha-synuclein in PD pathogenesis, and the mechanisms of iron and alpha-synuclein interaction.

Topics: alpha-Synuclein; Humans; Iron; Parkinson Disease

Alpha-synuclein belongs to the class of intrinsically disordered proteins lacking a well-folded structure under physiological conditions. The conversion of alpha-synuclein from a soluble monomer to an insoluble fibril may underlie the neurodegeneration associated with Parkinson's disease (PD). Although the exact mechanism of alpha-synuclein toxicity is still unknown, it has been proposed that alpha-synuclein disturbs membrane structure, leading to increased membrane permeability and eventual cell death. This review highlights the significant role played by fluorescence techniques in unraveling the nature of interactions between alpha-synuclein and membranes and its implications in PD.

Topics: alpha-Synuclein; Amino Acid Sequence; Cell Membrane; Humans; Models, Molecular; Parkinson Disease; Protein Conformation

Topics: alpha-Synuclein; Animals; Female; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease

In this review, we consider the use of nonhuman primate (NHP) models of Parkinson's disease (PD) produced using viral-mediated gene delivery and information they provide in comparison to other model systems in rodents and NHPs. To date, rodent and NHP PD models have found it difficult to fully recapitulate the human disorder and, therefore, provide little actual insight into disease progression. The viral-mediated gene delivery method for α-synuclein has been shown to produce a parkinsonian rodent and NHP. This novel viral-mediated gene transfer model in the NHP appears to provide a significant advance beyond neurotoxicant models, by more closely mimicking the more chronic time course of developed behavioral deterioration and neuropathology. Although we agree that the use of these novel methods inducing parkinsonian NHPs may provide relevant treatment insights, beyond those of more standard PD models, we remain cautious as to the preclinical models' ability to predict outcomes in human trials. In specific cases of certain novel medical therapeutics, therefore, we also consider the phase 0 clinical trial as offering an alternative to the currently non-predictive preclinical models, including those in the NHP.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Gene Transfer Techniques; Macaca; Parkinson Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease, with a strong genetic component to both the familial and sporadic forms. The cardinal motor symptoms of the disease result from the loss of dopamine (DA) neurons in the midbrain. There is currently no cure for PD and improved methods for modelling the disease are required in order to develop more effective therapeutic interventions. Patient-derived induced pluripotent stem cells (iPSCs) carry the genetic background of the donor, enabling accurate modelling of genetic diseases in vitro. Various human iPSCs from patients suffering different genetic forms of PD have been differentiated into DA neurons and demonstrated signs of the pathophysiology of PD in vitro. The examination of key cellular pathways such as calcium regulation and autophagy indicate that disease-associated genetic variants may have important implications for cellular function. This review examines and critiques how DA neurons from patient iPSCs have been used to model PD in vitro, and what iPSCs might hold for the future of PD research. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

Topics: alpha-Synuclein; Cell Differentiation; Dopaminergic Neurons; Glucosylceramidase; Humans; Induced Pluripotent Stem Cells; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Models, Genetic; Mutation; Parkinson Disease; Protein Kinases; Protein Serine-Threonine Kinases; Ubiquitin-Protein Ligases

Parkinson's disease is a common neurodegenerative disease characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta and the formation of α-synuclein aggregates found in Lewy bodies throughout the brain. Several α-synuclein transgenic mouse models have been generated, as well as viral-mediated overexpression of wild-type and mutated α-synuclein to mimic the disease and to delineate the pathogenic pathway of α-synuclein-mediated toxicity and neurodegeneration. In this review, we will recapitulate what we have learned about the function of α-synuclein and α-synuclein-mediated toxicity through studies of transgenic animal models, inducible animal models and viral-based models.

Topics: alpha-Synuclein; Animals; Animals, Genetically Modified; Disease Models, Animal; Humans; Parkinson Disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by bradykinesia, rigidity, resting tremor, and postural instability. Neuropathologically, intracellular aggregates of α-synuclein in Lewy bodies and Lewy neurites appear in particular brain areas according to a sequence of stages. Clinical diagnosis is usually established when motor symptoms are evident (corresponding to Braak stage III or later), years or even decades after onset of the disease. Research at early stages is therefore essential to understand the etiology of PD and improve treatment. Although classically considered as a motor disease, non-motor symptoms have recently gained interest. Olfactory deficits are among the earliest non-motor features of PD. Interestingly, α-synuclein deposits are present in the olfactory bulb and anterior olfactory nucleus at Braak stage I. Several lines of evidence have led to proposals that PD pathology spreads by a prion-like mechanism via the olfactory and vagal systems to the substantia nigra. In this context, current data on the temporal appearance of α-synuclein aggregates in the olfactory system of both humans and transgenic mice are of particular relevance. In addition to the proposed retrograde nigral involvement via brainstem nuclei, olfactory pathways could potentially reach the substantia nigra, and the possibility of centrifugal progression warrants investigation. This review analyzes the involvement of α-synuclein in different elements of the olfactory system, in both humans and transgenic models, from the hodological perspective of possible anterograde and/or retrograde progression of this proteinopathy within the olfactory system and beyond-to the substantia nigra and the remainder of the central and peripheral nervous systems.

Topics: alpha-Synuclein; Animals; Humans; Olfactory Bulb; Olfactory Pathways; Parkinson Disease

Accumulation of α-synuclein is key to the pathogenesis of Parkinson's disease (PD), though the exact mechanisms involved in its toxicity are still subject to debate. Increased α-synuclein expression or reduced degradation may play a role in the proteotoxicity observed in PD. Here we review the mechanisms of α-synuclein ubiquitination by different E3 ubiquitin-ligases, and its degradation via the proteasome, autophagy and lysosomes. Activators of α- synuclein ubiquitination and degradation pathways represent a plausible strategy to decrease α-synuclein burden in the disease. Nevertheless, since proteasomes and autophagy might be impaired in the disease, and because proteolytic impairment causes the accumulation of monoubiquitinated α-synuclein and the formation of toxic inclusions, compounds that promote α-synuclein monoubiquitination should be used in concert with compounds that boost these proteolytic pathways. This combined approach may therefore ease the accumulation of α-synuclein in PD and may represent a promising new avenue for the development of novel treatments for the disease.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Humans; Parkinson Disease; Ubiquitination

Misfolding and pathogenic aggregation of α-synuclein (αSyn) is a hallmark of familial and sporadic Parkinson's disease, but the physiological state of the protein in cells remains unsettled. We have further examined our hypothesis that endogenous αSyn can occur in normal cells as a metastable, helically folded tetramer, not solely as the unfolded monomer long thought to be its native form. At this meeting, we reviewed our recent approaches for trapping αSyn in intact cells via in vivo crosslinking, a 5-step purification of αSyn from normal human brain, and the generation of new monoclonal antibodies to αSyn that enable general and oligomer-selective ELISAs. Crosslinking in intact living cells confirmed that αSyn occurs in the cytosol of neurons and non-neural cells in substantial part as metastable tetramers and related oligomers, plus varying amounts of free monomers. The non-pathogenic homolog, β-synuclein, forms closely similar oligomeric assemblies, suggesting that the oligomers we observe for αSyn are also physiological. In contrast to other normal oligomeric proteins (e.g., DJ-1), αSyn tetramers dissociate rapidly to monomers upon conventional cell lysis but are retained partially as tetramers if cells are lysed at high protein concentrations ('molecular crowding'). Thus, αSyn exists natively as helical tetramers that are in dynamic equilibrium with unfolded monomers. The tetramers appear relatively resistant to aggregation, in contrast to monomers, which may give rise to fibrillar inclusions.

Topics: alpha-Synuclein; Animals; Brain; Humans; Parkinson Disease

The aging risk factor for Parkinson's disease is described in terms of specific disease markers including mitochondrial and gene dysfunctions relevant to energy metabolism. This review details evidence for the ability of nutritional agents to manage these aging risk factors. The combination of alpha lipoic acid, acetyl-l-carnitine, coenzyme Q10, and melatonin supports energy metabolism via carbohydrate and fatty acid utilization, assists electron transport and adenosine triphosphate synthesis, counters oxidative and nitrosative stress, and raises defenses against protein misfolding, inflammatory stimuli, iron, and other endogenous or xenobiotic toxins. These effects are supported by gene expression via the antioxidant response element (ARE; Keap/Nrf2 pathway), and by peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1 alpha), a transcription coactivator, which regulates gene expression for energy metabolism and mitochondrial biogenesis, and maintains the structural integrity of mitochondria. The effectiveness and synergies of the combination against disease risks are discussed in relation to gene action, dopamine cell loss, and the accumulation and spread of pathology via misfolded alpha-synuclein. In addition there are potential synergies to support a neurorestorative role via glial derived neurotrophic factor expression.

Topics: Acetylcarnitine; Adenosine Triphosphate; Aging; alpha-Synuclein; Antioxidant Response Elements; Carbohydrate Metabolism; Electron Transport; Energy Metabolism; Fatty Acids; Glial Cell Line-Derived Neurotrophic Factor; Humans; Inflammation; Melatonin; Mitochondria; Nitric Oxide; Oxidative Stress; Parkinson Disease; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Proteostasis Deficiencies; Risk Factors; Thioctic Acid; Transcription Factors; Ubiquinone

Genetic studies over the past 15 years have revolutionized our understanding towards the etiology of Parkinson's disease (PD). These studies have discovered many disease-linked genetic loci (PARK 1 to 18), which are now being interrogated for cellular pathways contributing to PD. Various pathogenic pathways were proposed but validation of each pathway awaits rigorous experimental testing. Here we review recent progress in understanding the influence of disease risk genes on cellular functions, specifically, autophagy pathways. Autophagy is a cell self-eating, lysosomal degradation system that plays an important role in cell homeostasis and survival. Neurons are post-mitotic cells and particularly vulnerable to the impairment of autophagic degradation due to their inability to redistribute damaged proteins and organelles to daughter cells. Emerging evidence has implicated dysfunctional autophagy in a growing number of neurodegenerative diseases including PD. We will also discuss the prospect of intervening autophagy pathways as a potential strategy to treat PD.

Topics: alpha-Synuclein; Animals; Autophagy; Genetic Predisposition to Disease; Humans; Parkinson Disease

Parkinson's disease (PD) and multiple system atrophy (MSA) are progressive neurodegenerative disorders classified as synucleinopathies, which are defined by the presence of α-synuclein protein pathology. Genetic studies have identified a total of 18 PARK loci that are associated with PD. The SNCA gene encodes the α-synuclein protein. The first pathogenic α-synuclein p.A53T substitution was discovered in 1997; this was followed by the identification of p.A30P and p.E46K pathogenic substitutions in 1998 and 2004, respectively. In the last year, two possible α-synuclein pathogenic substitutions, p.A18T and p.A29S, and two probable pathogenic substitutions, p.H50Q and p.G51D have been nominated. Next-generation sequencing approaches in familial PD have identified mutations in the VPS35 gene. A VPS35 p.D620N substitution remains the only confirmed pathogenic substitution. A second synucleinopathy, MSA, originally was considered a sporadic condition with little or no familial aggregation. However, recessive COQ2 mutations recently were nominated to be the genetic cause in a subset of familial and sporadic MSA cases. Further studies on the clinicogenetics and pathology of parkinsonian disorders will facilitate clarification of the molecular characteristics and pathomechanisms underlying these disorders.

Topics: Alkyl and Aryl Transferases; alpha-Synuclein; History, 20th Century; History, 21st Century; Humans; Multiple System Atrophy; Mutation; Parkinson Disease

There has been a tremendous development since a regional progression of pathology in subjects with Lewy bodies (LB) was initially proposed 30 years ago. The entity of dementia with Lewy bodies has been acknowledged, the main protein constituent of LBs--aggregated α-synuclein (αS)--has been identified and a stepwise progression of the pathology has been reported. Implementation of the staging strategies published provides a common ground for handling a case with a suspected α-synucleinopathy. It is always important to state the staging strategy implemented while assessing a case, as the strategy applied might influence both the reported stage of LB pathology and, ultimately, the final diagnosis of the patient.

Topics: alpha-Synuclein; Disease Progression; Humans; Lewy Bodies; Parkinson Disease

α-Synucleinopathies are neurodegenerative diseases characterised by the abnormal accumulation of α-synuclein aggregates in neurons, nerve fibres or glial cells. While small amounts of these α-synuclein pathologies can occur in some neurologically normal individuals who do not have associated neurodegeneration, the absence of neurodegeneration in such individuals precludes them from having a degenerative α-synucleinopathy, and it has yet to be established whether such individuals have a form of preclinical disease. There are three main types of α-synucleinopathy, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), with other rare disorders also having α-synuclein pathologies, such as various neuroaxonal dystrophies. Multiple clinical phenotypes exist for each of the three main α-synucleinopathies, with these phenotypes differing in the dynamic distribution of their underlying neuropathologies. Identifying the factors involved in causing different α-synuclein phenotypes may ultimately lead to more targeted therapeutics as well as more accurate clinical prognosis.

Topics: alpha-Synuclein; Humans; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Phenotype

The quantification of α-synuclein (αSyn) in cerebrospinal fluid (CSF) has been proposed as a diagnostic biomarker for Parkinson's disease and other αSyn-related diseases, such as multiple system atrophy and dementia with Lewy bodies. Most studies show decreased levels of αSyn in diseased CSF samples compared to control samples, but discrepant findings and overlapping values have been a major limitation for the use of CSF αSyn as a biomarker. This review addresses the current knowledge and investigates whether CSF αSyn is an ideal biomarker that can detect fundamental neuropathology features. It will also discuss whether CSF αSyn has been validated in neuropathologically confirmed cases, whether it shows a diagnostic sensitivity and whether it has a specificity above 80%. The review of current literature will also determine if sampling CSF αSyn is reliable, reproducible, noninvasive, simple to perform, inexpensive, and whether it has been investigated by at least two independent studies. CSF αSyn appears to meet most of these criteria, which have been proposed for ideal biomarkers, but further validation of this and other markers is needed to best introduce a panel of biomarkers in the early and differential diagnosis of Parkinson's disease.

Topics: alpha-Synuclein; Biomarkers; Humans; Parkinson Disease

Lewy bodies (LBs) and Lewy neurites (LNs), comprised of alpha-synuclein (aSyn), are intraneuronal inclusions that characterize Parkinson's disease. Although the association between the extent of Lewy pathology and clinical symptoms is well established, how these proteinaceous deposits originate and target selectively vulnerable cell populations is unknown. Our knowledge of their role in PD pathogenesis is also limited. Here, we summarize recent findings demonstrating this pathology can be experimentally transmitted between animals by misfolded forms of aSyn that are capable of initiating and inducing LB and LN inclusion formation through a self-propagating mechanism reminiscent of prions. "Seeded" LBs and LNs in animal models also spread to multiple connected nuclei in a predictable pattern, recapitulating a phenomenon observed during human PD progression, leading to the dysfunction and degeneration of afflicted neurons. These models provide new perspectives on how this and other misfolded proteins may contribute to neurodegeneration in human disease.

Topics: alpha-Synuclein; Animals; Disease Progression; Humans; Lewy Bodies; Lewy Body Disease; Models, Biological; Parkinson Disease; Proteostasis Deficiencies

An accurate early diagnostic test for Parkinson's disease (PD) is a critical unmet need. Recently, independent groups using different histological techniques have reported that the presence of alpha-synuclein (α-syn) in colonic biopsy tissue is able to distinguish living patients with PD from those without the disease. In addition, a further study has suggested that the presence of α-syn in colonic biopsy tissue may be evident in early or even prodromal PD. However, several questions remain regarding the translation of these findings into using the assessment of α-syn deposition in the enteric nervous system as a diagnostic biomarker for prodromal PD. Here we address critical issues related to the location and quantification of enteric α-syn, detection of α-syn with currently available histological techniques, timing of detection of α-syn deposition, and, most crucially, whether enteric α-syn can distinguish those with PD from both healthy individuals and individuals with other related diseases. We conclude that, although enteric α-syn is a very exciting prospect, further studies will be vital to determine whether enteric α-syn deposition has the potential to be the biomarker for prodromal PD that the field so desperately seeks.

Topics: alpha-Synuclein; Biomarkers; Colon; Enteric Nervous System; Humans; Parkinson Disease; Prodromal Symptoms

Neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD), constitute a major worldwide health problem. Several hypothesis have been put forth to elucidate the basis of onset and pathogenesis of AD and PD; however, till date, none of these seems to clearly elucidate the complex pathoetiology of these disorders. Notably, copper dyshomeostasis has been shown to underlie the pathophysiology of several neurodegenerative diseases including AD and PD. Numerous studies have concluded beyond doubt that imbalance in copper homeostatic mechanisms in conjunction with aging causes an acceleration in the copper toxicity elicited oxidative stress, which is detrimental to the central nervous system. Amyloid precursor protein and α-synuclein protein involved in AD and PD are copper binding proteins, respectively. In this review, we have discussed the possible association of copper metabolism proteins with AD and PD along with briefly outlining the expanding proportion of "copper interactome" in human biology. Using network biology, we found that copper metabolism proteins, superoxide dismutase 1 and ceruloplasmin may represent direct and indirect link with AD and PD, respectively.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Ceruloplasmin; Copper; Humans; Parkinson Disease; Predictive Value of Tests; Superoxide Dismutase; Superoxide Dismutase-1

Parkinson's disease (PD), one of the most frequent neurodegenerative disorders, is a progressive multi-organ proteinopathy caused by misfolded α-synuclein (αSyn) with variegated motor and nonmotor deficits owing to a spreading process of synaptic and neuronal loss in the nervous system. The motor core deficits of PD including rigidity, akinesia, rest tremor, and postural instability are attributed to the loss of dopaminergic nigrostriatal system, while the nonmotor alterations, such as hyposmia, autonomic and other dysfunctions frequently antedating motor symptoms are linked to widespread distribution of αSyn in the central, autonomic and peripheral nervous system and multiple organs. Recent studies have shown that αSyn aggregation in presynaptic terminals that predates the formation of Lewy bodies (LB), the characteristic markers of PD, is a key event in the pathogenesis of PD and other synucleinopathies. Progress in our understanding of the underlying mechanisms include insights into the functional organization of the basal ganglia and related cortico-subcortical circuits and their relations with morphological and pathophysiological lesions in the nervous system. The pathomechanisms underlying the cardinal motor abnormalities and nonmotor manifestations are briefly reviewed.

Topics: alpha-Synuclein; Brain; Humans; Lewy Bodies; Parkinson Disease; Proteostasis Deficiencies

Immunotherapy targeting α-synuclein has evolved as a potential therapeutic strategy for neurodegenerative diseases, such as Parkinson's disease, and initial studies on cellular and animal models have shown promising results. α-synuclein vaccination of transgenic mice reduced the number of brain inclusions, whereas passive immunization studies demonstrated that antibodies against the C-terminus of α-synuclein can pass the blood-brain barrier and affect the pathology. In addition, preliminary evidence suggests that transgenic mice treated with an antibody directed against α-synuclein oligomers/protofibrils resulted in reduced levels of such species in the CNS. The underlying mechanisms of immunotherapy are not yet fully understood, but may include antibody-mediated clearance of pre-existing aggregates, prevention of protein propagation between cells and microglia-dependent protein clearance. Thus, immunotherapy targeting α-synuclein holds promise, but needs to be further developed as a future disease-modifying treatment in Parkinson's disease and other α-synucleinopathies.

Topics: alpha-Synuclein; Animals; Antibodies, Monoclonal; Humans; Immunotherapy; Lewy Bodies; Lewy Body Disease; Mice; Mice, Transgenic; Molecular Targeted Therapy; Parkinson Disease; Unfolded Protein Response

Parkinson's disease (PD) is a neurodegenerative disorder that affects movement and is caused by the death of the dopaminergic neurons in the compact part of the substantia nigra. Its diagnosis is essentially clinical, but although the signs and symptoms of PD are well known, the rate of diagnostic error is relatively high. It is estimated that 10-30% of patients initially diagnosed with PD are later reclassified. This disease has a high prevalence beyond the age of 60, and one of its biggest problems is that it is diagnosed when the degenerative process is already at a very advanced stage. Therefore, it is necessary to look for other biomarkers that make it possible to carry out an early diagnosis of PD, follow up its development, distinguish it from other related pathologies (parkinsonisms) and help monitor the effect of novel therapies. The fact that there are mutations that lead to PD, as well as polygenetic combinations that can act as risk factors, suggests the possibility of measuring the proteins resulting from the expression of these genes in peripheral tissues. And once their sensitivity and specificity have been proved they could be used as biomarkers for PD, even in the early phases of the disease. The aim of this work is to focus on a detailed review of the main candidate proteomic biomarkers researched to date by discussing the most recent literature.. Biomarcadores proteomicos en la enfermedad de Parkinson.. La enfermedad de Parkinson (EP) es un trastorno neurodegenerativo que afecta al movimiento, cuya causa es la muerte de las neuronas dopaminergicas de la parte compacta de la sustancia negra. El diagnostico es fundamentalmente clinico, pero, a pesar de que los signos y sintomas de la EP se conocen bien, el error diagnostico es relativamente alto. Se calcula que un 10-30% de los pacientes inicialmente diagnosticados de EP se reclasifican posteriormente. Esta enfermedad tiene una alta prevalencia a partir de los 60 años, y uno de los mayores problemas que tiene es que su diagnostico se hace cuando el proceso degenerativo esta muy avanzado. Por tanto, es necesaria la busqueda de biomarcadores que permitan un diagnostico precoz de la EP, seguir su progresion, diferenciarla de otras patologias relacionadas (parkinsonismos) y que ayuden a monitorizar el efecto de nuevas terapias. El hecho de que existan mutaciones que conducen a la EP, asi como combinaciones poligenicas que pueden actuar como factores de riesgo, sugiere que es posible analizar las proteinas resultantes de la expresion de estos genes en tejidos perifericos, que, una vez demostrada su sensibilidad y especificidad, podrian utilizarse como biomarcadores de la EP, incluso en fases iniciales de la enfermedad. El objetivo del presente trabajo es centrarse en una revision detallada de los principales biomarcadores proteomicos candidatos investigados hasta el momento, discutiendo la literatura mas reciente.

Topics: Aged; alpha-Synuclein; Amyloid beta-Peptides; Biomarkers; Dopaminergic Neurons; Early Diagnosis; Female; Forecasting; Humans; Inflammation Mediators; Intracellular Signaling Peptides and Proteins; Lewy Bodies; Lysosomes; Male; Microglia; Middle Aged; Oncogene Proteins; Parkinson Disease; Peptide Fragments; Prevalence; Protein Deglycase DJ-1; Proteomics; Sensitivity and Specificity; Substantia Nigra

The lysosomal enzyme glucocerebrosidase, encoded by the glucocerebrosidase gene, is involved in the breakdown of glucocerebroside into glucose and ceramide. Lysosomal build-up of the substrate glucocerebroside occurs in cells of the reticulo-endothelial system in patients with Gaucher disease, a rare lysosomal storage disorder caused by the recessively inherited deficiency of glucocerebrosidase. Gaucher disease has a broad clinical phenotypic spectrum, divided into non-neuronopathic and neuronopathic forms. Like many monogenic diseases, the correlation between clinical manifestations and molecular genotype is not straightforward. There is now a well-established clinical association between mutations in the glucocerebrosidase gene and the development of more prevalent multifactorial disorders including Parkinson's disease and other synucleinopathies. In this review we discuss recent studies advancing our understanding of the cellular relationship between glucocerebrosidase and α-synuclein, the potential impact of established and emerging therapeutics for Gaucher disease for the treatment of the synucleinopathies, and the role of lysosomal pathways in the pathogenesis of these neurodegenerative disorders.

Topics: alpha-Synuclein; Gaucher Disease; Genetic Association Studies; Genotype; Glucosylceramidase; Humans; Mutation; Parkinson Disease; Phenotype

Protein misfolding is an intrinsic aspect of normal folding within the complex cellular environment. Its effects are minimized in living system by the action of a range of protective mechanisms including molecular chaperones and quality control systems. According to the current growing research, protein misfolding is a recognized key feature of most neurodegenerative diseases. Extensive biochemical, neuropathological, and genetic evidence suggest that the cerebral accumulation of amyloid fibrils is the central event in the pathogenesis of neurodegenerative disorders. In the first part of this review we have discussed the general course of action of folding and misfolding of the proteins. Later part of this review gives an outline regarding the role of protein misfolding in the molecular and cellular mechanisms in the pathogenesis of Alzheimer's and Parkinson along with their treatment possibilities. Finally, we have mentioned about the recent findings in neurodegenerative diseases.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Autophagy; Heat-Shock Proteins; Humans; Molecular Chaperones; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurofibrillary Tangles; Parkinson Disease; Phosphorylation; Plaque, Amyloid; Proteasome Endopeptidase Complex; Protein Folding; Protein Processing, Post-Translational; Ubiquitination; Unfolded Protein Response

Neurodegenerative diseases such as Parkinson׳s disease are progressive disorders of the nervous system that affect the function and maintenance of specific neuronal populations. While most disease cases are sporadic with no known cause, a small percentage of disease cases are caused by inherited genetic mutations. The identification of genes associated with the familial forms of the diseases and subsequent studies of proteins encoded by the disease genes in cellular or animal models have offered much-needed insights into the molecular and cellular mechanisms underlying disease pathogenesis. Recent studies of the familial Parkinson׳s disease genes have emphasized the importance of RNA metabolism, particularly mRNA translation, in the disease process. It is anticipated that continued studies on the role of RNA metabolism in Parkinson׳s disease will offer unifying mechanisms for understanding the cause of neuronal dysfunction and degeneration and facilitate the development of novel and rational strategies for treating this debilitating disease.

Topics: alpha-Synuclein; Animals; Eukaryotic Initiation Factor-4G; Humans; Intracellular Signaling Peptides and Proteins; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Oncogene Proteins; Parkinson Disease; Protein Biosynthesis; Protein Deglycase DJ-1; Protein Kinases; Protein Serine-Threonine Kinases; RNA; Signal Transduction; Ubiquitin-Protein Ligases

Therapeutic efforts in neurodegenerative diseases have been very challenging, particularly due to a lack of validated and mechanism-based therapeutic targets and biomarkers. The basic idea underlying the novel therapeutic approaches reviewed here is that by exploring the molecular basis of neurodegeneration in a rare lysosomal disease such as Gaucher's disease (GD), new molecular targets will be identified for therapeutic development in common synucleinopathies. Accumulation of α-synuclein plays a key role in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies, suggesting that improved clearance of α-synuclein may be of therapeutic benefit. To achieve this goal, it is important to identify specific mechanisms and targets involved in the clearance of α-synuclein. Recent discovery of clinical, genetic, and pathological linkage between GD and PD offers a unique opportunity to examine lysosomal glucocerebrosidase, an enzyme mutated in GD, for development of targeted therapies in synucleinopathies. While modulation of glucocerebrosidase and glycolipid metabolism offers a viable approach to treating disorders associated with synuclein accumulation, the compounds described to date either lack the ability to penetrate the CNS or have off-target effects that may counteract or limit their capabilities to mediate the desired pharmacological action. However, recent emergence of selective inhibitors of glycosphingolipid biosynthesis and noninhibitory pharmacological chaperones of glycosphingolipid processing enzymes that gain access to the CNS provide a novel approach that may overcome some of the limitations of compounds reported to date. These new strategies may allow for development of targeted treatments for synucleinopathies that affect both children and adults.

Topics: Adolescent; Adult; alpha-Synuclein; Child; Child, Preschool; Gaucher Disease; Glucosylceramidase; Glycolipids; Humans; Lipid Metabolism; Mutation; Parkinson Disease

Parkinson disease is the second most common neurodegenerative disease in the world, but there is currently no available cure for it. Current treatments only alleviate some of the symptoms for a few years, but they become ineffective in the long run and do not stop the disease. Therefore it is of outmost importance to develop therapeutic strategies that can prevent, stop, or cure Parkinson disease. A very promising target for these therapies is the peripheral immune system due to its probable involvement in the disease and its potential as a tool to modulate neuroinflammation. But for such strategies to be successful, we need to understand the particular state of the peripheral immune system during Parkinson disease in order to avoid its weaknesses. In this review we examine the available data regarding how dopamine regulates the peripheral immune system and how this regulation is affected in Parkinson disease; the specific cytokine profiles observed during disease progression and the alterations documented to date in patients' peripheral blood mononuclear cells. We also review the different strategies used in Parkinson disease animal models to modulate the adaptive immune response to salvage dopaminergic neurons from cell death. After analyzing the evidence, we hypothesize the need to prime the immune system to restore natural tolerance against α-synuclein in Parkinson disease, including at the same time B and T cells, so that T cells can reprogram microglia activation to a beneficial pattern and B cell/IgG can help neurons cope with the pathological forms of α-synuclein.

Topics: alpha-Synuclein; Animals; Cytokines; Disease Models, Animal; Dopamine; Humans; Immune System; Immune Tolerance; Immunologic Factors; Leukocytes, Mononuclear; Parkinson Disease; Vaccination

Glycogen synthase kinase-3 (GSK-3) is a pleiotropic serine/threonine protein kinase found in almost all eukaryotes. It is structurally highly conserved and has been identified as a multifaceted enzyme affecting a wide range of biological functions, including gene expression and cellular processes. There are two closely related isoforms of GSK-3; GSK-3α and GSK-3β. The latter appears to play crucial roles in regulating the pathogenesis of diverse diseases, including neurodegenerative disease. The present review focuses on the involvement of this protein in Parkinson's disease (PD), a common neurodegenerative disorder characterized by the gradually progressive and selective loss of dopaminergic neurons, and by intracellular inclusions known as Lewy bodies (LBs) expressed in surviving neurons of the substantia nigra (SN). GSK-3β is involved in multiple signaling pathways and has several phosphorylation targets. Numerous apoptotic conditions can be facilitated by the GSK-3β signaling pathways. Studies have shown that GSK-3β inhibition protects the dopaminergic neurons from various stress-induced injuries, indicating the involvement of GSK-3β in PD pathogenesis. However, the underlying mechanisms of the protective effect of GSK-3β inhibition on dopaminergic neurons in PD is not completely understood. Multiple pathological events have been recognized to be responsible for the loss of dopaminergic neurons in PD, including mitochondrial dysfunction, oxidative stress, protein aggregation and neuroinflammation. The present review stresses the regulatory roles of GSK-3β in these events and in dopaminergic neuron degeneration, in an attempt to gain an improved understanding of the underlying mechanisms and to provide a potential effective therapeutic target for PD.

Topics: alpha-Synuclein; Animals; Apoptosis; Electron Transport Complex I; Fetal Proteins; Gene Expression Regulation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Inflammation; Mitochondria; Parkinson Disease; Reactive Oxygen Species; Signal Transduction; T-Box Domain Proteins

Parkinson's disease (PD) is neuropathologically characterized as an alpha-synucleinopathy. Alpha-synuclein-containing inclusions are stained as Lewy bodies and Lewy neurites in the brain, which are the pathological hallmark of PD. However, alpha-synuclein-containing inclusions in PD are not restricted to the central nervous system, but are also found in peripheral tissues. Alpha-synuclein levels can also be measured in body fluids. The aim of this study was to conduct a systematic review of available evidence to determine the utility of alpha-synuclein as a peripheral biomarker of PD. We searched PubMed (1948 to 26 May 2013), Embase (1974 to 26 May 2013), the Cochrane Library (up to 26 May 2013), LILACS (up to 26 May 2013) and CINAHL (up to 26 May 2013) for the studies of alpha-synuclein in peripheral tissues or body fluids in PD. A total of 49 studies fulfilled the search criteria. Peripheral tissues such as colonic mucosa showed a sensitivity of 42-90% and a specificity of 100%; submandibular salivary glands showed sensitivity and specificity of 100%; skin biopsy showed 19% sensitivity and 80% specificity in detecting alpha-synuclein pathology. CSF alpha-synuclein had 71-94% sensitivity and 25-53% specificity for distinguishing PD from controls. Plasma alpha-synuclein had 48-53% sensitivity and 69-85% specificity. Neither plasma nor CSF alpha-synuclein is presently a reliable marker of PD. This differs from alpha-synuclein in solid tissue samples of the enteric and autonomic nervous system, which offer some potential as a surrogate marker of brain synucleinopathy.

Topics: alpha-Synuclein; Biomarkers; Humans; Parkinson Disease

Parkinson's disease (PD) is a degenerative disease of the central nervous system, of which patomechanizm entirely is not clear. In the picture neuropathologically there is observed degeneration and loss of dopaminergic neurons, but also noradrenergic, serotonergic and cholinergic neurons in patients with PD. It is believed, that causes of PD are both environmental and genetic factors, associated mainly with mutations in the SNCA and PRKN genes, which may lead to changes in the structure of proteins such as alpha-synuclein (ASN) and Parkin. In neurons, disorders of the protein structure can lead to its aggregation and formation of soluble oligomers and insoluble filaments in the form of Lewy bodies and Lewy neuritis. In PD aggregation of ASN can be modulated by many factors like: oxidative stress, other neuronal proteins, Parkin, catecholamines especially dopamine, and mutations of SNCA gene. It also appears that some impact on the aggregation of ASN may have destabilizing factors of ASN tetramers. That, does ASN may become a new point for pharmacotherapy in PD.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Gene Expression; Humans; Mutation; Oxidative Stress; Parkinson Disease; Proteasome Endopeptidase Complex; Proteolysis; Ubiquitin-Protein Ligases

Despite active fundamental, translational and clinical research, no therapeutic intervention has yet shown convincing effects on disease progression in Parkinson's disease (PD) patients. Indeed, several disease-modification trials failed or proved to be inconclusive due to lack of consistency between clinical rating scales and putative surrogate markers of disease progression, or confounding symptomatic effects of the tested compound. Multiple system atrophy (MSA) is a rapidly progressing orphan disorder leading to severe motor disability within a few years. Together with PD and dementia with Lewy bodies (DLB), MSA belongs to the synucleinopathies, a group of neurodegenerative disorders characterized by the abnormal accumulation of alpha-synuclein. Crucial milestones have been reached for successfully conducting clinical intervention trials in a large number of patients with MSA. In this personal view, we will review evidence, and discuss why MSA could prove the most relevant clinical model for assessing treatments that target mechanisms operating in all synucleinopathies.

Topics: alpha-Synuclein; Brain; Clinical Trials as Topic; Humans; Multiple System Atrophy; Parkinson Disease

Parkinson disease (PD; MIM 168600) is the second most common progressive neurodegenerative disorder characterized by a variety of motor and non-motor features. To date, at least 20 loci and 15 disease-causing genes for parkinsonism have been identified. Among them, the α-synuclein (SNCA) gene was associated with PARK1/PARK4. Point mutations, duplications and triplications in the SNCA gene cause a rare dominant form of PD in familial and sporadic PD cases. The α-synuclein protein, a member of the synuclein family, is abundantly expressed in the brain. The protein is the major component of Lewy bodies and Lewy neurites in dopaminergic neurons in PD. Further understanding of its role in the pathogenesis of PD through various genetic techniques and animal models will likely provide new insights into our understanding, therapy and prevention of PD.

Topics: alpha-Synuclein; Animals; Caenorhabditis elegans; Disease Models, Animal; Drosophila; Genetic Variation; Haplorhini; Humans; Mice; Parkinson Disease; Rats

Calcium (Ca(2+)) is an almost universal second messenger that regulates important activities of all eukaryotic cells. It is of critical importance to neurons, which have developed extensive and intricate pathways to couple the Ca(2+) signal to their biochemical machinery. In particular, Ca(2+) participates in the transmission of the depolarizing signal and contributes to synaptic activity. During aging and in neurodegenerative disease processes, the ability of neurons to maintain an adequate energy level can be compromised, thus impacting on Ca(2+) homeostasis. In Parkinson's disease (PD), many signs of neurodegeneration result from compromised mitochondrial function attributable to specific effects of toxins on the mitochondrial respiratory chain and/or to genetic mutations. Despite these effects being present in almost all cell types, a distinguishing feature of PD is the extreme selectivity of cell loss, which is restricted to the dopaminergic neurons in the ventral portion of the substantia nigra pars compacta. Many hypotheses have been proposed to explain such selectivity, but only recently it has been convincingly shown that the innate autonomous activity of these neurons, which is sustained by their specific Cav1.3 L-type channel pore-forming subunit, is responsible for the generation of basal metabolic stress that, under physiological conditions, is compensated by mitochondrial buffering. However, when mitochondria function becomes even partially compromised (because of aging, exposure to environmental factors or genetic mutations), the metabolic stress overwhelms the protective mechanisms, and the process of neurodegeneration is engaged. The characteristics of Ca(2+) handling in neurons of the substantia nigra pars compacta and the possible involvement of PD-related proteins in the control of Ca(2+) homeostasis will be discussed in this review.

Topics: alpha-Synuclein; Animals; Brain; Calcium Signaling; Dopaminergic Neurons; Humans; Intracellular Signaling Peptides and Proteins; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mitochondria; Oncogene Proteins; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Protein Serine-Threonine Kinases; Ubiquitin-Protein Ligases

Alpha-Synuclein protein(alphaS) aggregates from a monomer to assemblies such as oligomers, protofibrils, and mature fibrils. The early intermediate aggregate, that is, the oligomer, has been reported to be the most toxic species. We recently reported that melatonin inhibits alphaS aggregation, including protofibril and oligomer formations. While the alphaS concentration in cerebrospinal fluid was reported to significantly decrease in patients with Parkinson's disease (PD) and dementia with Lewy bodies, there have been reports that the alphaS oligomer concentration was elevated in the cerebrospinal fluid of PD patients. Moreover, it was reported that the alphaS oligomer concentration was also elevated in the blood of PD patients. Further studies may establish alphaS in cerebrospinal fluid and blood as a biomarker of alpha-synucleinopathies, including PD.

Topics: alpha-Synuclein; Animals; Endoribonucleases; Humans; Ion Channels; Lewy Bodies; Lewy Body Disease; Parkinson Disease

The degeneration of dopaminergic neurons in Parkinson's disease (PD) is suggested to be associated with the generation of cytotoxic products from dopamine (DA) metabolism and the formation of fibrillar inclusions of the protein α-synuclein (AS). Despite of the role of AS in the pathogenesis of PD is not completely understood, the stabilization of nontoxic aggregates could represent a potential therapeutic route. In respect to the DA metabolism, a well-established strategy is the inhibition of the enzyme monoamine oxidase, which is responsible to catalyze the major route of inactivation of neurotransmitters. Although pharmacological strategies to treat different aspects of the parkinsonian condition are under investigation, the development of multifunctional molecules that act simultaneously on different targets associated to PD has gained attention only recently. In this work we examine the biochemical properties of synthetic and natural molecules that are capable of interfering on both DA system (via monoamine oxidase inhibition) and AS fibrillation.

Topics: alpha-Synuclein; Dopaminergic Neurons; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease

Prions are self-propagating protein conformers that cause a variety of neurodegenerative disorders in humans and animals. Mouse models have played key roles in deciphering the biology of prions and in assessing candidate therapeutics. The development of transgenic mice that form prions spontaneously in the brain has advanced our understanding of sporadic and genetic prion diseases. Furthermore, the realization that many proteins can become prions has necessitated the development of mouse models for assessing the potential transmissibility of common neurodegenerative diseases. As the universe of prion diseases continues to expand, mouse models will remain crucial for interrogating these devastating illnesses.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Mutation; Parkinson Disease; Prion Diseases; Prions; tau Proteins

Neurodegenerative diseases are characterized by the aggregation of misfolded proteins in the brain. Among these disorders are the prion diseases, which are transmissible, and in which the misfolded proteins ("prions") are also the infectious agent. Increasingly, it appears that misfolded proteins in Alzheimer and Parkinson diseases and the tauopathies also propagate in a "prion-like" manner. However, the association between prion formation, spread, and neurotoxicity is not clear. Recently, we showed that in prion disease, protein misfolding leads to neurodegeneration through dysregulation of generic proteostatic mechanisms, specifically, the unfolded protein response. Genetic and pharmacological manipulation of the unfolded protein response was neuroprotective despite continuing prion replication, hence dissociating this from neurotoxicity. The data have clear implications for treatment across the spectrum of these disorders, targeting pathogenic processes downstream of protein misfolding.

Topics: Adenine; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; eIF-2 Kinase; Humans; Indoles; Neurodegenerative Diseases; Parkinson Disease; Prion Diseases; Prions; Protein Conformation; Protein Kinase Inhibitors; tau Proteins; Tauopathies; Unfolded Protein Response

There is evidence that the α-synucleinopathies Parkinson's disease (PD) and the Parkinson variant of multiple system atrophy (MSA-P) overlap at multiple levels. Both disorders are characterized by deposition of abnormally phosphorylated fibrillar α-synuclein within the central nervous system suggesting shared pathophysiological mechanisms. Despite the considerable clinical overlap in the early disease stages, MSA-P, in contrast to PD, is fatal and rapidly progressive. Moreover recent clinical studies have shown that surrogate markers of disease progression can be quantified easily and may reliably depict the rapid course of MSA. We therefore posit that, MSA-P may be exploited as a filter barrier in the development of disease-modifying therapeutic strategies targeting common pathophysiological mechanisms of α-synucleinopathies. This approach might reduce the number of negative phase III clinical trials, and, in turn, shift the available resources to earlier development stages, thereby increasing the number of candidate compounds validated.

Topics: alpha-Synuclein; Drug Discovery; Humans; Multiple System Atrophy; Parkinson Disease

Leucine-rich repeat kinase 2 (LRRK2) is a large, ubiquitous protein of unknown function. Mutations in the gene encoding LRRK2 have been linked to familial and sporadic Parkinson's disease (PD) cases. The LRRK2 protein is a single polypeptide that displays GTPase and kinase activity. Kinase and GTPase domains are involved in different cellular signaling pathways. Despite several experimental studies associating LRRK2 protein with various intracellular membranes and vesicular structures such as endosomal/lysosomal compartments, the mitochondrial outer membrane, lipid rafts, microtubule-associated vesicles, the golgi complex, and the endoplasmic reticulum its broader physiologic function(s) remain unidentified. Additionally, the cellular distribution of LRRK2 may indicate its role in several different pathways, such as the ubiquitin-proteasome system, the autophagic-lysosomal pathway, intracellular trafficking, and mitochondrial dysfunction. This review discusses potential mechanisms through which LRRK2 may mediate neurodegeneration and cause PD.

Topics: alpha-Synuclein; Animals; Cytoskeleton; Genetic Predisposition to Disease; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mitochondria; Mutation; Parkinson Disease; Protein Serine-Threonine Kinases; Proteins

Parkinson disease (PD) is a progressive neurodegenerative movement disorder characterized pathologically by abnormal SNCA/α-synuclein protein inclusions in neurons. Impaired lysosomal autophagic degradation of cellular proteins is implicated in PD pathogenesis and progression. Heterozygous GBA mutations, encoding lysosomal GBA/glucocerebrosidase (glucosidase, β, acid), are the greatest genetic risk factor for PD, and reduced GBA and SNCA accumulation are related in PD models. Here we review our recent human brain tissue study demonstrating that GBA deficits in sporadic PD are related to the early accumulation of SNCA, and dysregulation of chaperone-mediated autophagy (CMA) pathways and lipid metabolism.

Topics: alpha-Synuclein; Autophagy; Glucosylceramidase; Humans; Lipid Metabolism; Molecular Chaperones; Parkinson Disease

Several neurodegenerative diseases involve loss of catecholamine neurons-Parkinson disease is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are vulnerable in PD and related disorders has been mysterious. Accumulating evidence supports the concept of "autotoxicity"-inherent cytotoxicity of catecholamines and their metabolites in the cells in which they are produced. According to the "catecholaldehyde hypothesis" for the pathogenesis of Parkinson disease, long-term increased build-up of 3,4-dihydroxyphenylacetaldehyde (DOPAL), the catecholaldehyde metabolite of dopamine, causes or contributes to the eventual death of dopaminergic neurons. Lewy bodies, a neuropathologic hallmark of PD, contain precipitated alpha-synuclein. Bases for the tendency of alpha-synuclein to precipitate in the cytoplasm of catecholaminergic neurons have also been mysterious. Since DOPAL potently oligomerizes and aggregates alpha-synuclein, the catecholaldehyde hypothesis provides a link between alpha-synucleinopathy and catecholamine neuron loss in Lewy body diseases. The concept developed here is that DOPAL and alpha-synuclein are nodes in a complex nexus of interacting homeostatic systems. Dysfunctions of several processes, including decreased vesicular sequestration of cytoplasmic catecholamines, decreased aldehyde dehydrogenase activity, and oligomerization of alpha-synuclein, lead to conversion from the stability afforded by negative feedback regulation to the instability, degeneration, and system failure caused by induction of positive feedback loops. These dysfunctions result from diverse combinations of genetic predispositions, environmental exposures, stress, and time. The notion of catecholamine autotoxicity has several implications for treatment, disease modification, and prevention. Conversely, disease modification clinical trials would provide key tests of the catecholaldehyde hypothesis.

Topics: 3,4-Dihydroxyphenylacetic Acid; alpha-Synuclein; Animals; Apoptosis; Catecholamines; Humans; Lipid Peroxidation; Neurodegenerative Diseases; Neurons; Oxidation-Reduction; Parkinson Disease

Parkin (Parkinson juvenile disease protein 2) is a ~52 kDa (426 amino acid) enzyme protein, encoded by PARK2 gene and located on the 6q chromosome. It plays an important role in the ubiquitin-proteasome system and acts as a regulator of protein breakdown. Parkin is located in the cytoplasma until a sustained depolarization occurs as a result of which it is translocated to the mitochondrial surface and induces the degradation of various membrane proteins which are candidates for mitophagia. Parkin is essential for cellular mitochondrial integrity. Parkin mutation leads to the accumulation of missfolded, aggregated proteins and degenerated mitochondria. The role of these changes in the pathomechanism of neurodegenerative diseases is well-known. It was a general belief for a long time that Parkinson's disease is without genetic component a sporadic disease. In 1997 a point mutation was, however, discovered in the α-synuclein gene, which caused dominantly inherited parkinsonism. At least 10 other genes were thereafter detected the mutation or deletion of which cause monogenic parkinsonism. Parkin mutation is responsible for about 50% of familial cases and for 10 to 20% of youth cases. According to the present views the improper regulation of protein aggregation and a dysfunction of the ubiquitin-proteasome system may be the common pathway of sporadic and hereditary Parkinson's disease. In the future it might have therapeutic value that parkin has versatile neuroprotective activity (against α-synuclein toxicity, proteasomal dysfunction, oxidative stress, kainite-induced and dopamine-mediated toxicity) as a result of which any reduction of parkin level or activity may cause damage in neuronal integrity.

Topics: alpha-Synuclein; Animals; Dopamine; Dopaminergic Neurons; Gene-Environment Interaction; Humans; Intracellular Signaling Peptides and Proteins; Kainic Acid; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mitochondria; Oncogene Proteins; Oxidative Stress; Parkinson Disease; Point Mutation; Proteasome Endopeptidase Complex; Protein Deglycase DJ-1; Protein Kinases; Protein Serine-Threonine Kinases; Ubiquitin; Ubiquitin-Protein Ligases

α-synuclein, a small protein (140 amino acids) encoded by the SNCA gene is the best known isoform of the synuclein protein family. Though its physiological role is still not fully clarified, there is growing experimental evidence for a causal role of α-synuclein in the so-called conformational-neurodegenerative diseases. Conformational changes in the structure of the native soluble protein form insoluble neurotoxic aggregates and finally contribute to the formation of inclusion Lewy-bodies and Lewy-neurites. Neurodegeneration first hits the olfactory system, the peripheral autonomic nervous system, the enteric nervous system and the dorsal vagal motoneurons. The middle stage of the disease hits the dopaminergic neurons of the substantia nigra; and the neocortex is affected only in the late stage of the disease. This precise order of neurodegeneration is not always valid, but increases the likelihood that Lewy-bodies and neurodegenaration spread to intact areas in a prion-like way. Prions are infectious proteins which do not contain nucleic acids and cause diseases because they form toxic aggregates and filaments by misfolding in a β-sheet-rich conformation. The misfolded protein behaves like a template inducing conformational change in the wild type proteins causing cross-reaction and leading to neurodegeneration. Later, the defective proteins may infect healthy nerve cells, thus neurodegeneration is extended. Growing experimental evidence shows that monomers and aggregates of α-synuclein are secreted via exocytosis from damaged nerve cells and taken up via endocytosis by healthy nerve cells furnishing evidence for the prion-like role of α-synuclein.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Endocytosis; Exocytosis; Humans; Lewy Bodies; Nerve Degeneration; Neuroprotective Agents; Parkinson Disease; Prions; Protein Structure, Secondary; Selegiline

The misfolding and aggregation of endogenous proteins in the central nervous system is a neuropathological hallmark of Alzheimer's disease (AD), Parkinson's disease (PD), as well as prion diseases. A molecular mechanism referred to as "nucleation-dependent aggregation" is thought to underlie this neuropathological phenomenon. According to this concept, disease-associated protein particles act as nuclei, or seeds, that recruit cellular proteins and incorporate them, in a misfolded form, into their growing aggregate structure. Experimental studies have shown that the aggregation of the AD-associated proteins amyloid-β (Aβ) and tau, and of the PD-associated protein α-synuclein, can be stimulated in laboratory animal models by intracerebral (i.c.) injection of inocula containing aggregated species of the respective proteins. This has raised the question of whether AD or PD can be transmitted, like certain human prion diseases, between individuals by self-propagating protein particles potentially present on medical instruments or in blood or blood products. While the i.c. injection of inocula containing AD- or PD-associated protein aggregates was found to cause neuronal damage and clinical abnormalities (e.g., motor impairments) in some animal models, none of the studies published so far provided evidence for a transmission of severe or even fatal disease. In addition, available epidemiological data do not indicate a transmissibility of AD or PD between humans. The findings published so far on the effects of experimentally transmitted AD- or PD-associated protein seeds do not suggest specific precautionary measures in the context of hemotherapy, but call for vigilance in transfusion medicine and other medical areas.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Central Nervous System; Humans; Models, Molecular; Parkinson Disease; Prions; Protein Folding; tau Proteins

Neurodegenerative diseases characterized by the presence of α-synuclein-a hallmark of pathologic inclusions termed Lewy bodies-include Parkinson's disease, dementia with Lewy bodies, and multiple-system atrophy. Although motor symptoms are related to the altered presynaptic dopaminergic function in these diseases, the appearance of α-synuclein inclusions precedes the involvement of the nigrostriatal dopaminergic pathway. Hence, the most accurate and earliest definition of premotor Parkinson's disease ought to rely on imaging α-synuclein rather than dopaminergic changes. Moreover, dopaminergic imaging has been controversial in monitoring the effects of investigational disease-modifying drugs. For these clinical trials, intense interest in longitudinally imaging α-synuclein as the primary pathologic process has led to efforts toward developing a suitable radiotracer for this key protein. An overview of the present α-synuclein radiotracer development scenario is presented here.

Topics: alpha-Synuclein; Animals; Humans; Molecular Imaging; Neurodegenerative Diseases; Parkinson Disease; Positron-Emission Tomography

Parkinson's disease (PD) is a neurodegenerative disorder, which results from the loss of specific population of neurons, namely the pigmented dopamine secreting neurons of the substnatia nigra pars compatica (SNPc) of midbrain. The exact cause leading to nigrostriatal cell death is not yet known. In recent years, accumulating evidence from the identified molecular events in familial forms of PD contributed much to unraveling the mechanisms by which dopaminergic neurons die in PD and which hopefully would lead to the development of therapeutic interventions. Several major disease causing pathways were identified so far. These are possibly interconnected and some genes share a common pathway e.g., (i) defects in ubiquitin-proteasome pathway and protein misfolding and aggregation caused by α-synuclein and Parkin gene defects; (ii) defects in mitochondrial morphology and function in PINK1/Parkin and DJ-1 mutations; (iii) increased susceptibility to cellular oxidative stress which appear to underlie defects in α-synuclein, Parkin and DJ-1 genes. The aim of this review is to shed light on the molecular mechanisms by which mutations in familial-linked genes cause PD.

Topics: alpha-Synuclein; Humans; Intracellular Signaling Peptides and Proteins; Mutation; Nerve Degeneration; Oncogene Proteins; Parkinson Disease; Protein Deglycase DJ-1; Signal Transduction; Ubiquitin-Protein Ligases

In Parkinson's disease (PD) and other synucleinopathies, chronic neurodegeneration occurs within different areas of the central nervous system leading to progressive motor and nonmotor symptoms. The symptomatic treatment options that are currently available do not slow or halt disease progression. This highlights the need of a better understanding of disease mechanisms and disease models. The generation of newborn neurons in the adult hippocampus and in the subventricular zone/olfactory bulb system is affected by many different regulators and possibly involved in memory processing, depression, and olfaction, symptoms which commonly occur in PD. The pathology of the adult neurogenic niches in human PD patients is still mostly elusive, but different preclinical models have shown profound alterations of adult neurogenesis. Alterations in stem cell proliferation, differentiation, and survival as well as neurite outgrowth and spine formation have been related to different aspects in PD pathogenesis. Therefore, neurogenesis in the adult brain provides an ideal model to study disease mechanisms and compounds. In addition, adult newborn neurons have been proposed as a source of endogenous repair. Herein, we review current knowledge about the adult neurogenic niches in PD and highlight areas of future research.

Topics: Adult; alpha-Synuclein; Animals; Animals, Genetically Modified; Cell Survival; Disease Models, Animal; Female; Hippocampus; Humans; Lateral Ventricles; Male; Neurogenesis; Neuronal Plasticity; Neurons; Parkinson Disease

Parkinson's disease (PD) is primarily characterized by motor abnormalities, but cognitive changes also occur in the early and late stages of the disease process. In PD patients, cognitive dysfunction is associated with reduced quality of life, as well as increased morbidity and mortality, resulting in increases in caregiver burden, and health-related costs. Therefore, safe and effective approaches are needed to treat cognitive dysfunction in PD patients. The underlying pathophysiology of cognitive dysfunction is complex and not fully understood, however. α-Synuclein, amyloid-related proteins, and cholinergic deficits have been reported to partially contribute to cognitive dysfunction. Changes in cortical dopamine (DA) content may also be responsible for early cognitive changes in patients with PD. Certainly, dopaminergic afferents to the frontal cortex degenerate in PD, and there is a reduction of DA content in the prefrontal cortex (PFC). It has also been reported that PFC dopaminergic input plays an important role in working memory performance. Moreover, PFC DA levels and working memory performance are significantly reduced by a 6-hydroxydopamine lesion in the PFC of a rat. Recent findings in the areas of pharmacological manipulation and genetic ablation suggest that the adenosine A2A receptor is also related to cognitive functions, especially working memory. In addition, the blockade of adenosine A2A receptors reverses cognitive dysfunction in PFC-lesioned rats, and this blocking effect may be due to an increase in PFC DA content. Therefore, adenosine A2A receptor antagonists not only improve motor performance, but they may also lead to improved cognitive function in those with PD.

Topics: Adenosine A2 Receptor Antagonists; alpha-Synuclein; Amyloid beta-Peptides; Animals; Cerebral Cortex; Cognition Disorders; Humans; Parkinson Disease; Rats

The review covers the current literature on the pathogenetic mechanisms of dementia in older patients with Parkinson's disease(PD). The author emphasizes that, along with the degeneration of brain structures, there are vascular changes that promote the development of mixed dementia. Neurodegenerative process and cerebrovascular pathology are in reciprocal relationship and their combination enhances the development of cognitive impairment. The cholinergic deficit is one of the key patterns of pathogenesis of dementia in PD. In this connection, the efficacy of acetylcholinesterase inhibitors: galantamine (reminil),neuromidin, rivastigmine in the treatment of PD patients with dementia is discussed. It is concluded, that correction of vascular risk factors should be administered to older PD patients with mixed dementia. A multidimensional approach with the close relationship between neurologists, psychiatrists and therapists is needed.

Topics: Aging; alpha-Synuclein; Aminoquinolines; Cholinergic Neurons; Cholinesterase Inhibitors; Dementia; Female; Galantamine; Humans; Male; Mutation; Parkinson Disease; Phenylcarbamates; Protein Kinases; Rivastigmine

Alpha-Synuclein (αSyn) is a 14 kDa pre-synaptic protein predominantly expressed in various regions of brain comprising neocortex, hippocampus, striatum, thalamus and cerebellum. αSyn aggregates have special neuropathologic relevance for comprehending Parkinson's disease (PD) and other synucleopathies due to the presence of αSyn aggregates in brain of patients suffering from these diseases. Direct relationship between PD and various single nuclear polymorphisms of αSyn further displays an inherent significance of mutated αSyn in increasing the risk for developing PD. So far, various theories have been emerged to explain αSyn mediated neuronal cell toxicity seen in patients with PD, including interaction of αSyn aggregates with biomolecules, vesicle dystrafficking, augmented oxidative stress, mitochondrial dysfunction, and disruption of synaptic function. Despite the advances in understanding of PD pathophysiology, current available treatments are still aiming at giving symptomatic relief. Lately, PD vaccines against αSyn aggregates are also being considered. However, various other avenues for e.g. post-translational and conformational modifications of αSyn, effect of cellular small molecules such as polyamines and osmolytes on αSyn aggregation, still remain unexplored and we believe that therapeutics directed at these ignored targets will surface as a successful combinational therapy for PD. Additionally, understanding mechanisms behind the interplay between PD and other health conditions, such as Gaucher's disease, Cardiovascular disorders, Hypertension, Homocystinuria, Type-II Diabetes, and Cancer are also speculated to provide great insight for novel therapeutic interventions. In the current review, we have precisely discussed all these ignored avenues with their possible clinical implications. Link between PD and other associated diseases has also been extensively reviewed.

Topics: alpha-Synuclein; Animals; Antiparkinson Agents; Humans; Parkinson Disease

Alpha-synuclein plays a key role in the pathology of synucleinopathies including Parkinson's disease (PD) and multiple system atrophy (MSA). However, whether alpha-synuclein level in cerebrospinal fluid (CSF) could distinguish synucleinopathies from progressive supranuclear palsy (PSP) is still a contentious issue. A comprehensive literature search yielded nine eligible studies. We expressed the between-group difference of the concentration of alpha-synuclein in CSF as the standardized mean difference. The proportion of variation attributable to heterogeneity was computed and expressed as I(2) . Nine studies involved 537 controls, 843 PD, 130 MSA, and 98 PSP patients. The overall effect of PD on alpha-synuclein in CSF was significantly different from normal control or disease control (standardized mean difference = -0.67, P < 0.00001). These studies were heterogeneous (I(2) = 40%). Alpha-synuclein in CSF in MSA was significantly reduced relative to controls with heterogeneous studies (standardized mean difference = -0.75, P < 0.0001; I(2) = 62%). In contrast, no significant difference of alpha-synuclein in CSF was observed between PSP and controls with heterogeneous studies (standardized mean difference = -0.28, P = 0.13; I(2) = 53%). Alpha-synuclein in CSF was significantly reduced in synucleinopathies compared with PSP ("PD vs. PSP": standardized mean difference = -0.38, P = 0.001; "MSA vs. PSP": standardized mean difference = -0.66, P < 0.00001). The included studies were homogeneous (I(2) = 0%). Our study showed that alpha-synuclein levels in CSF in synucleinopathies was significantly lower than in PSP. This finding provides insights into the pathophysiological difference between synucleinopathies and PSP as well as possibility of development of a tool for differential diagnosis between MSA and PSP using enzyme-linked immunosorbent assay (ELISA) and similar methods.

Topics: Aged; alpha-Synuclein; Female; Humans; Male; Middle Aged; Multiple System Atrophy; Parkinson Disease; Supranuclear Palsy, Progressive

Parkinson's disease (PD) is not only characterized by motor disturbances but also, by cognitive, sensory, psychiatric and autonomic dysfunction. It has been proposed that some of these symptoms might be related to the widespread pathology of α-synuclein (α-syn) aggregation in different nuclei of the central and peripheral nervous system. However, the pathogenic formation of α-syn aggregates in different brain areas of PD patients is poorly understood. Most experimental models of PD are valuable to assess specific aspects of its pathogenesis, such as toxin-induced dopaminergic neurodegeneration. However, new models are required that reflect the widespread and progressive formation of α-syn aggregates in different brain areas. Such α-syn aggregation is induced in only a few animal models, for example perikaryon inclusions are found in rats administered rotenone, aggregates with a neuritic morphology develop in mice overexpressing either mutated or wild-type α-syn, and in Smad3 deficient mice, aggregates form extensively in the perikaryon and neurites of specific brain nuclei. In this review we focus on α-syn aggregation in the human disorder, its genetics and the availability of experimental models. Indeed, evidences show that dopamine (DA) metabolism may be related to α-syn and its conformational plasticity, suggesting an interesting link between the two pathological hallmarks of PD: dopaminergic neurodegeneration and Lewy body (LB) formation.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Dopamine; Glucosylceramidase; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Bodies; Mice; Mutation; Parkinson Disease; Protein Aggregates; Protein Serine-Threonine Kinases; Rats

Alpha-synuclein (ASYN) is a major constituent of the typical protein aggregates observed in several neurodegenerative diseases that are collectively referred to as synucleinopathies. A causal involvement of ASYN in the initiation and progression of neurological diseases is suggested by observations indicating that single-point (e.g., A30P, A53T) or multiplication mutations of the gene encoding for ASYN cause early onset forms of Parkinson's disease (PD). The relative regional specificity of ASYN pathology is still a riddle that cannot be simply explained by its expression pattern. Also, transgenic over-expression of ASYN in mice does not recapitulate the typical dopaminergic neuronal death observed in PD. Thus, additional factors must contribute to ASYN-related toxicity. For instance, synucleinopathies are usually associated with inflammation and elevated levels of oxidative stress in affected brain areas. In turn, these conditions favor oxidative modifications of ASYN. Among these modifications, nitration of tyrosine residues, formation of covalent ASYN dimers, as well as methionine sulfoxidations are prominent examples that are observed in post-mortem PD brain sections. Oxidative modifications can affect ASYN aggregation, as well as its binding to biological membranes. This would affect neurotransmitter recycling, mitochondrial function and dynamics (fission/fusion), ASYN's degradation within a cell and, possibly, the transfer of modified ASYN to adjacent cells. Here, we propose a model on how covalent modifications of ASYN link energy stress, altered proteostasis, and oxidative stress, three major pathogenic processes involved in PD progression. Moreover, we hypothesize that ASYN may act physiologically as a catalytically regenerated scavenger of oxidants in healthy cells, thus performing an important protective role prior to the onset of disease or during aging.

Topics: alpha-Synuclein; Humans; Nerve Degeneration; Nitric Oxide; Oxidative Stress; Parkinson Disease; Peroxynitrous Acid

Alpha synuclein (αsyn) fibrils are found in the Lewy Bodies of patients with Parkinson's disease (PD). The aggregation of the αsyn monomer to soluble oligomers and insoluble fibril aggregates is believed to be one of the causes of PD. Recently, the view of the native state of αsyn as a monomeric ensemble was challenged by a report suggesting that αsyn exists in its native state as a helical tetramer. This review reports on our current understanding of αsyn within the context of these recent developments and describes the work performed by a number of groups to address the monomer/tetramer debate. A number of in depth studies have subsequently shown that both non-acetylated and acetylated αsyn purified under mild conditions are primarily monomer. A description of the accessible states of acetylated αsyn monomer and the ability of αsyn to self-associate is explored.

Topics: Acetylation; alpha-Synuclein; Humans; Lewy Bodies; Parkinson Disease; Protein Conformation; Protein Multimerization; Protein Structure, Secondary

The role of neuroinflammation and the adaptive immune system in PD (Parkinson's disease) has been the subject of intense investigation in recent years, both in animal models of parkinsonism and in post-mortem PD brains. However, how these processes relate to and modulate α-syn (α-synuclein) pathology and microglia activation is still poorly understood. Specifically, how the peripheral immune system interacts, regulates and/or is induced by neuroinflammatory processes taking place during PD is still undetermined. We present herein a comprehensive review of the features and impact that neuroinflamation has on neurodegeneration in different animal models of nigral cell death, how this neuroinflammation relates to microglia activation and the way microglia respond to α-syn in vivo. We also discuss a possible role for the peripheral immune system in animal models of parkinsonism, how these findings relate to the state of microglia activation observed in these animal models and how these findings compare with what has been observed in humans with PD. Together, the available data points to the need for development of dual therapeutic strategies that modulate microglia activation to change not only the way microglia interact with the peripheral immune system, but also to modulate the manner in which microglia respond to encounters with α-syn. Lastly, we discuss the immune-modulatory strategies currently under investigation in animal models of parkinsonism and the degree to which one might expect their outcomes to translate faithfully to a clinical setting.

Topics: alpha-Synuclein; Animals; Brain; Disease Models, Animal; Humans; Lymphocytes; Microglia; Neurons; Parkinson Disease

Chronic exposure to particulate matter air pollution is known to cause inflammation leading to respiratory- and cardiovascular-related sickness and death. Mexico City Metropolitan Area children exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, and innate and adaptive immune responses. Early dysregulated neuroinflammation, brain microvascular damage, production of potent vasoconstrictors, and perturbations in the integrity of the neurovascular unit likely contribute to progressive neurodegenerative processes. The accumulation of misfolded proteins coincides with the anatomical distribution observed in the early stages of both Alzheimer's and Parkinson's diseases. We contend misfolding of hyperphosphorylated tau (HPπ), alpha-synuclein, and beta-amyloid could represent a compensatory early protective response to the sustained systemic and brain inflammation. However, we favor the view that the chronic systemic and brain dysregulated inflammation and the diffuse vascular damage contribute to the establishment of neurodegenerative processes with childhood clinical manifestations. Friend turns Foe early; therefore, implementation of neuroprotective measures to ameliorate or stop the inflammatory and neurodegenerative processes is warranted in exposed children. Epidemiological, cognitive, structural, and functional neuroimaging and mechanistic studies into the association between air pollution exposures and the development of neuroinflammation and neurodegeneration in children are of pressing importance for public health.

Topics: Adolescent; Adult; Age of Onset; Air Pollution; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain; Child; Cities; Female; Humans; Male; Mexico; Oxidative Stress; Parkinson Disease; Particulate Matter; Protein Folding; tau Proteins; Urban Population; Young Adult

Increased α-synuclein levels and mutations in mitochondria-associated proteins both cause familial Parkinson's disease (PD), and synuclein and mitochondria also play central, but poorly understood, roles in the pathogenesis of idiopathic PD. A fraction of synuclein interacts with mitochondria, and synuclein can produce mitochondrial fragmentation and impair mitochondrial complex I activity. However, the consequences of these mitochondrial changes for bioenergetic and other mitochondrial functions remain poorly defined, as does the role of synuclein-mitochondria interactions in the normal and pathologic effects of synuclein. Understanding the functional consequences of synuclein's interactions with mitochondria is likely to provide important insights into disease pathophysiology, and may also reveal therapeutic strategies.

Topics: alpha-Synuclein; Animals; Electron Transport Complex I; Humans; Mitochondria; Parkinson Disease

Parkinson's disease is characterized by α-synuclein pathology in the form of Lewy bodies and Lewy neurites. Braak et al described the spatial and temporal spread of α-synuclein pathology in Parkinson's disease. Recent experimental studies have demonstrated that α-synuclein can transfer from cell to cell. In this review, we highlight the involvement of α-synuclein in Parkinson's disease and in Braak's staging of Parkinson's disease pathology. We discuss whether a prion-like mechanism of α-synuclein spread might contribute to Parkinson's disease pathology. We describe recent studies investigating cell-to-cell transfer of α-synuclein and focus our review on the long-distance axonal transport of α-synuclein along neurons.

Topics: Algorithms; alpha-Synuclein; Animals; Axonal Transport; Axons; Central Nervous System; Digestive System; Disease Progression; Humans; Parkinson Disease; Prions

Parkinson's disease is characterized by intracellular proteinaceous depositions known as Lewy bodies. These largely consist of the protein α-synuclein, whose physiological function remains unclear, but mutations and overexpression of the protein have been shown to cause early onset cases of Parkinson's disease. Deregulation of α-synuclein biology causes neurodegeneration and impaired neuronal trafficking, hinting at a possible contribution to the pathological mechanism. Recent studies produced some evidence hinting at the involvement of several regulators of the transport machinery such as Rab GTPases and SNARE proteins, but also shown that α-synuclein can be propagated between cells. Here, we discuss the molecular interplay of α-synuclein with the intracellular transport machinery, its consequences, and the implications for disease mechanisms.

Topics: alpha-Synuclein; Animals; Axons; Biological Transport; Humans; Parkinson Disease; rab GTP-Binding Proteins; SNARE Proteins; Synaptic Vesicles

The aggregation of the protein alpha-synuclein (α-SYN) is believed to be a critical event in Parkinson's disease (PD). α-SYN is characterized by a remarkable conformational plasticity, adopting different conformations depending on the environment. In vitro, α-SYN lacks a well-defined structure. Therefore, it was classified as an 'intrinsically disordered protein'. A debate has recently begun over how α-SYN behaves in the cell: is it an intrinsically disordered protein or a stable tetramer with a low propensity for aggregation? In this review, we discuss the aggregation of α-SYN and describe factors that influence this process and their potential relevance in PD pathogenesis. We address the ways in which aggregated α-SYN mediates toxicity and might lead to PD, and propose possible therapeutic strategies.

Topics: alpha-Synuclein; Animals; Humans; Parkinson Disease; Protein Conformation

The past decade has witnessed huge advances in our understanding of the genetics underlying Parkinson's disease. Identifying commonalities in the biological function of genes linked to Parkinson's provides an opportunity to elucidate pathways that lead to neuronal degeneration and eventually to disease. We propose that the genetic forms of Parkinson's disease largely associated with α-synuclein-positive neuropathology (SNCA, LRRK2, and GBA) are brought together by involvement in the autophagy/lysosomal pathway and that this represents a unifying pathway to disease in these cases.

Topics: alpha-Synuclein; Animals; Autophagy; Humans; Lysosomes; Models, Biological; Nerve Degeneration; Parkinson Disease

Parkinson disease (PD) is a chronic and progressive neurological disease associated with a loss of dopaminergic neurons. In most cases the disease is sporadic but genetically inherited cases also exist. One of the major pathological features of PD is the presence of aggregates that localize in neuronal cytoplasm as Lewy bodies, mainly composed of α-synuclein (α-syn) and ubiquitin. The selective degeneration of dopaminergic neurons suggests that dopamine itself may contribute to the neurodegenerative process in PD. Furthermore, mitochondrial dysfunction and oxidative stress constitute key pathogenic events of this disorder. Thus, in this review we give an actual perspective to classical pathways involving these two mechanisms of neurodegeneration, including the role of dopamine in sporadic and familial PD, as well as in the case of abuse of amphetamine-type drugs. Mutations in genes related to familial PD causing autosomal dominant or recessive forms may also have crucial effects on mitochondrial morphology, function, and oxidative stress. Environmental factors, such as MPTP and rotenone, have been reported to induce selective degeneration of the nigrostriatal pathways leading to α-syn-positive inclusions, possibly by inhibiting mitochondrial complex I of the respiratory chain and subsequently increasing oxidative stress. Recently, increased risk for PD was found in amphetamine users. Amphetamine drugs have effects similar to those of other environmental factors for PD, because long-term exposure to these drugs leads to dopamine depletion. Moreover, amphetamine neurotoxicity involves α-syn aggregation, mitochondrial dysfunction, and oxidative stress. Therefore, dopamine and related oxidative stress, as well as mitochondrial dysfunction, seem to be common links between PD and amphetamine neurotoxicity.

Topics: alpha-Synuclein; Amphetamine; Dopaminergic Neurons; Humans; Illicit Drugs; Mitochondria; Oxidative Stress; Parkinson Disease; Parkinson Disease, Secondary; Substantia Nigra; Ubiquitin

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of a protein called α-synuclein (α-syn) into inclusions known as lewy bodies (LB) within neurons. This accumulation is also due to insufficient formation and activity of dopamine produced in certain neurons within the substantia nigra. Lewy bodies are the pathological hallmark of the idiopathic disorder and the cascade that allows α-synuclein to misfold, aggregate and form these inclusions has been the subject of intensive research. Targeting these early steps of oligomerization is one of the main therapeutic approaches in order to develop neurodegenerative-modifying agents. Because the folding and refolding of alpha synuclein is the key point of this cascade, we are interested in this review to summarize the role of some molecular chaperones proteins such as Hsp70, Hsp90 and small heat shock proteins (sHsp) and Hsp 104. Hsp70 and its co-chaperone, Hsp70 and small heat shock proteins can prevent neurodegeneration by preventing α-syn misfolding, oligomerization and aggregation in vitro and in Parkinson disease animal models. Hsp104 is able to resolve disordered protein aggregates and cross beta amyloid conformers. Together, these chaperones have a complementary effect and can be a target for therapeutic intervention in PD.

Topics: alpha-Synuclein; Animals; Biomarkers; Heat-Shock Proteins; Humans; Lewy Bodies; Molecular Chaperones; Parkinson Disease; Protein Folding; Proteostasis Deficiencies

Parkinson disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease (AD). The formation of the cytoplasmic inclusions named "Lewy bodies" in the brain, considered to be a marker for neuronal degeneration in PD and dementia with Lewy bodies. However, Lewy bodies (LBs) are also observed in approximately 60 percent of both sporadic and familial cases with AD. LBs consist of fibrils mainly formed by post-translational modified α-synuclein (α-syn) protein. The modifications can be truncation, phosphorylation, nitration and mono-, di-, or tri-ubiquitination. Development of disease seems to be linked to events that increase the concentration of α-syn or cause its chemical modification, either of which can accelerate α-syn aggregation. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or modified forms of α-syn. As the aggregation of α-syn in the brain has been strongly implicated as a critical step in the development of several neurodegenerative diseases, the current search for disease-modifying drugs is focused on modification of the process of α-syn deposition in the brain. Recently researchers have screened and designed various molecules that are selectively focused on inhibiting or preventing α-syn aggregation and toxicity. Another strategy that has emerged is to target α-syn expression as a potential therapy for neurodegenerative diseases associated with LBs.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Humans; Lewy Bodies; Neurodegenerative Diseases; Parkinson Disease

Dementia is increasingly being recognized in cases of Parkinson's disease (PD); such cases are termed PD dementia (PDD). The spread of fibrillar α-synuclein (α-syn) pathology from the brainstem to limbic and neocortical structures seems to be the strongest neuropathological correlate of emerging dementia in PD. In addition, up to 50% of patients with PDD also develop sufficient numbers of amyloid-β plaques and tau-containing neurofibrillary tangles for a secondary diagnosis of Alzheimer's disease, and these pathologies may act synergistically with α-syn pathology to confer a worse prognosis. An understanding of the relationships between these three distinct pathologies and their resultant clinical phenotypes is crucial for the development of effective disease-modifying treatments for PD and PDD.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Brain; Humans; Neurons; Parkinson Disease; tau Proteins

Over the past decade, the baker's yeast Saccharomyces cerevisiae has proven to be a useful model system to investigate fundamental questions concerning the pathogenic role of human proteins in neurodegenerative diseases such as Parkinson's disease (PD). These so-called humanized yeast models for PD initially focused on α -synuclein, which plays a key role in the etiology of PD. Upon expression of this human protein in the baker's yeast Saccharomyces cerevisiae, the events leading to aggregation and the molecular mechanisms that result in cellular toxicity are faithfully reproduced. More recently, a similar model to study the presumed pathobiology of the α -synuclein interaction partner synphilin-1 has been established. In this review we will discuss recent advances using these humanized yeast models, pointing to new roles for cell wall integrity signaling, Ca(2+) homeostasis, mitophagy, and the cytoskeleton.

Topics: alpha-Synuclein; Humans; Parkinson Disease; Saccharomyces cerevisiae

The disappointments of a series of large anti-amyloid trials have brought home the point that until the driving force behind Alzheimer's disease, and the way it causes harm, are firmly established and accepted, researchers will remain ill-equipped to find a way to treat patients successfully. The origin of inflammation in neurodegenerative diseases is still an open question. We champion and expand the argument that a shift in intracellular location of α-synuclein, thereby moving a key methylation enzyme from the nucleus, provides global hypomethylation of patients' cerebral DNA that, through being sensed by TLR9, initiates production of the cytokines that drive these cerebral inflammatory states. After providing a background on the relevant inflammatory cytokines, this commentary then discusses many of the known alternatives to the primary amyloid argument of the pathogenesis of Alzheimer's disease, and the treatment approaches they provide. A key point to appreciate is the weight of evidence that inflammatory cytokines, largely through increasing insulin resistance and thereby reducing the strength of the ubiquitously important signaling mediated by insulin, bring together most of these treatments under development for neurodegenerative disease under the one roof. Moreover, the principles involved apply to a wide range of inflammatory diseases on both sides of the blood brain barrier.

Topics: alpha-Synuclein; Alzheimer Disease; Animals; Cytokines; DNA Methylation; Epigenesis, Genetic; Humans; Inflammation; Influenza, Human; Insulin Resistance; Lead; Mice; Neurodegenerative Diseases; Parkinson Disease; RNA, Untranslated; Toll-Like Receptor 9

The development of novel therapies against neurodegenerative disorders requires the ability to detect their early, presymptomatic manifestations in order to enable treatment before irreversible cellular damage occurs. Precocious signs indicative of neurodegeneration include characteristic changes in certain protein levels, which can be used as diagnostic biomarkers when they can be detected in fluids such as blood plasma or cerebrospinal fluid. In the case of synucleinopathies, cerebrospinal alpha-synuclein (α-syn) has attracted great interest as a potential biomarker; however, there is ongoing debate regarding the association between cerebrospinal α-syn levels and neurodegeneration in Parkinson disease and synucleinopathies. Post-translational modifications (PTMs) have emerged as important determinants of α-syn's physiological and pathological functions. Several PTMs are enriched within Lewy bodies and exist at higher levels in α-synucleinopathy brains, suggesting that certain modified forms of α-syn might be more relevant biomarkers than the total α-syn levels. However, the quantification of PTMs in bodily fluids poses several challenges. This review describes the limitations of current immunoassay-based α-syn quantification methods and highlights how these limitations can be overcome using novel mass-spectrometry-based assays. In addition, we describe how advances in chemical synthesis, which have enabled the preparation of α-syn proteins that are site-specifically modified at single or multiple residues, can facilitate the development of more accurate assays for detecting and quantifying α-syn PTMs in health and disease.

Topics: alpha-Synuclein; Antibodies, Monoclonal; Biomarkers; Chromatography, Liquid; Humans; Lewy Bodies; Mass Spectrometry; Neurodegenerative Diseases; Parkinson Disease; Peptide Fragments; Peptide Mapping; Phosphorylation; Protein Processing, Post-Translational; Proteolysis; Ubiquitination

Parkinson's disease (PD) is one of the most common degenerative disorders of the central nervous system that produces motor and non-motor symptoms. The majority of cases are idiopathic and characterized by the presence of Lewy bodies containing fibrillar α-synuclein. Small ubiquitin-related modifier (SUMO) immunoreactivity was observed among others in cases with PD. Key disease-associated proteins are SUMO-modified, linking this posttranslational modification to neurodegeneration. SUMOylation and SUMO-mediated mechanisms have been intensively studied in recent years, revealing nuclear and extranuclear functions for SUMO in a variety of cellular processes, including the regulation of transcriptional activity, modulation of signal transduction pathways, and response to cellular stress. This points to a role for SUMO more than just an antagonist to ubiquitin and proteasomal degradation. The identification of risk and age-at-onset gene loci was a breakthrough in PD and promoted the understanding of molecular mechanisms in the pathology. PD has been increasingly linked with mitochondrial dysfunction and impaired mitochondrial quality control. Interestingly, SUMO is involved in many of these processes and up-regulated in response to cellular stress, further emphasizing the importance of SUMOylation in physiology and disease.

Topics: alpha-Synuclein; Dopaminergic Neurons; Gene Expression Regulation; Humans; Intracellular Signaling Peptides and Proteins; Mitochondria; Nerve Tissue Proteins; Neurotoxins; Oncogene Proteins; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Proteasome Endopeptidase Complex; Protein Binding; Protein Deglycase DJ-1; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Transcription, Genetic; Ubiquitin; Ubiquitin-Protein Ligase Complexes; Ubiquitin-Protein Ligases

Parkinson's disease (PD) is a devastating neurodegenerative disease that affects over one million patients in the US. Yet, no disease modifying drugs exist, only those that temporarily alleviate symptoms. Because of its poorly defined and highly complex disease etiology, it is essential to embrace unbiased and innovative approaches for identifying new chemical entities that target the underlying toxicities associated with PD. Traditional target-based drug discovery paradigm can suffer from a bias toward a small number of potential targets. Phenotypic screening of both genetic and pharmacological PD models offers an alternative approach to discover compounds that target the initiating causes and effectors of cellular toxicity. The relative paucity of reported phenotypic screens illustrates the intrinsic difficulty in establishing model systems that are both biologically meaningful and adaptable to high-throughput screening. Parallel advances in PD models and in vivo screening technologies will help create opportunities for identifying new therapeutic leads with unanticipated, breakthrough mechanisms of action.

Topics: alpha-Synuclein; Animals; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Humans; Parkinson Disease; Phenotype; Yeasts

Gaucher disease (GD) is a lysosomal disorder caused by inherited deficiency of glucocerebrosidase (GCase), resulting in the accumulation of glucocerebroside in macrophages, termed "Gaucher cells," leading to multiorgan involvement, with hepatosplenomegaly, cytopenias, pulmonary hypertension, and skeletal complications. Various mutations, encoding the GCase gene, cause acute or chronic neuronopathic forms of the disease. The hallmark of GD is the macrophages infiltrating organs, bone marrow, and nervous system compromising their function by inflammation, infarcts, fibrosis, and neuronal damage. Coagulation abnormalities are frequent among GD patients due to reduced production and chronic consumption of coagulation factors. Splenic and bone infarcts often occur in GD patients, but hypercoagulability is not frequent. Detection of thrombophilic risk factors in GD patients may predict a more severe course of the disease. Clinical and genetic studies revealed an association between reduced GCase activity in carriers of GD mutations and GD patients and occurrence of Parkinson disease (PD) and showed that GCase gene mutations are risk factors for PD development. The mechanisms underlying the association of PD and GD are not yet elucidated and should be further explored, particularly the potential involvement of inflammation and coagulation in the neurovascular unit.

Topics: alpha-Synuclein; Blood Coagulation Factors; Gaucher Disease; Glucosylceramidase; Humans; Mutation; Parkinson Disease; Risk Factors; Thrombophilia

Recently published data demonstrated that increased release, oligomerization and toxicity of α-synuclein (ASN) is a key molecular process in pathophysiology of neurodegenerative diseases classified as synucleinopathies (e.g. Parkinson disease or Alzheimer's disease). It was proved that the excessive release of ASN into the extracellular space, driven by environmental factors as well as neurodegeneration, may have a significant role in the spread of the neurodegeneration process within the brain. Extracellular ASN was shown to be toxic both to neurons and glial cells and the mechanism of its action depends on the concentration of this protein in the extracellular space. Exogenous ASN leads to the activation of plasma membrane receptors, causes increased calcium influx, and stimulates the synthesis of proinflammatory cytokines and nitric oxide, which in turn leads to activation of programmed cell death. These data provide new insights into the involvement of ASN in the neurodegenerative diseases, and thus can serve effectively for the development of their new therapy.

Topics: alpha-Synuclein; Alzheimer Disease; Apoptosis; Brain; Cell Death; Extracellular Space; Humans; Neuroglia; Neurons; Nitric Oxide; Parkinson Disease

Oxidative stress plays an important role in the degeneration of dopaminergic neurons in Parkinson's disease (PD). Disruptions in the physiologic maintenance of the redox potential in neurons interfere with several biological processes, ultimately leading to cell death. Evidence has been developed for oxidative and nitrative damage to key cellular components in the PD substantia nigra. A number of sources and mechanisms for the generation of reactive oxygen species (ROS) are recognized including the metabolism of dopamine itself, mitochondrial dysfunction, iron, neuroinflammatory cells, calcium, and aging. PD causing gene products including DJ-1, PINK1, parkin, alpha-synuclein and LRRK2 also impact in complex ways mitochondrial function leading to exacerbation of ROS generation and susceptibility to oxidative stress. Additionally, cellular homeostatic processes including the ubiquitin-proteasome system and mitophagy are impacted by oxidative stress. It is apparent that the interplay between these various mechanisms contributes to neurodegeneration in PD as a feed forward scenario where primary insults lead to oxidative stress, which damages key cellular pathogenetic proteins that in turn cause more ROS production. Animal models of PD have yielded some insights into the molecular pathways of neuronal degeneration and highlighted previously unknown mechanisms by which oxidative stress contributes to PD. However, therapeutic attempts to target the general state of oxidative stress in clinical trials have failed to demonstrate an impact on disease progression. Recent knowledge gained about the specific mechanisms related to PD gene products that modulate ROS production and the response of neurons to stress may provide targeted new approaches towards neuroprotection.

Topics: alpha-Synuclein; Animals; Calcium; Dopamine; Dopaminergic Neurons; Glutathione; Humans; Intracellular Signaling Peptides and Proteins; Iron; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lipid Metabolism; Melanins; Mitochondria; Oncogene Proteins; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Protein Deglycase DJ-1; Protein Kinases; Protein Serine-Threonine Kinases; Ubiquitin; Ubiquitin-Protein Ligases

Many proteins associated with neurodegenerative diseases have poorly defined or unknown functions. α-Synuclein is one such protein which is associated with a range of diseases including Parkinson's disease. Now accepted as a metal-binding protein, α-synuclein's function could possibly be defined in relation to the binding of cofactors. It has been suggested recently that α-synuclein is able to reduce iron using copper as its catalytic centre. The consequence of this is that possibly the function of α-synuclein can now be defined. The evidence for this and the consequences for Parkinson's disease are discussed in the present review.

Topics: alpha-Synuclein; Animals; FMN Reductase; Humans; Parkinson Disease

Misfolded proteins and subsequent protein aggregation appears to underlie a significant fraction of neurodegenerative diseases including Parkinson's disease. One of the neuropathological hallmarks of Parkinson's disease is the presence of α-syn containing intracellular inclusions known as Lewy bodies and Lewy neurites. Intrabodies are antibody fragments that have been engineered to be expressed intracellularly. They can be directed towards specific target antigens present in various subcellular locations, and have shown promise in cancer, HIV, autoimmune diseases, and Huntington's disease. More recently they have been shown to modulate abnormalities caused by aggregated α-syn in cell culture. This mini-review mainly focuses on summarizing structural and cellular effects of intrabodies shown to have affinity for different forms of α-synuclein (monomeric, oligomeric and fibrillar), as well as those exhibiting affinity for particular residues of α-synuclein (e.g., the NAC region, C terminal region).

Topics: alpha-Synuclein; Antibodies; Humans; Lewy Bodies; Neuroprotective Agents; Parkinson Disease; Protein Engineering; Protein Folding

The pathogenesis of many neurodegenerative disorders arises in association with the misfolding and accumulation of a wide variety of proteins. Much emphasis has been placed on understanding the nature of these protein accumulations, including their composition, the process by which they are formed and the physiological impact they impose at cellular and, ultimately, organismal levels. Alpha-synuclein (ASYN) is the major component of protein inclusions known as Lewy bodies and Lewy neurites, which are the typical pathological hallmarks in disorders referred to as synucleinopathies. In addition, mutations or multiplications in the gene encoding for ASYN have also been shown to cause familial cases of PD, the most common synucleinopathy. Although the precise function of ASYN remains unclear, it appears to be involved in a vast array of cellular processes. Here, we review, in depth, a spectrum of cellular and molecular mechanisms that have been implicated in synucleinopathies. Importantly, detailed understanding of the biology/pathobiology of ASYN may enable the development of novel avenues for diagnosis and/or therapeutic intervention in synucleinopathies.

Topics: alpha-Synuclein; Animals; beta-Synuclein; Endoplasmic Reticulum; gamma-Synuclein; Humans; Lewy Bodies; Lewy Body Disease; Multiple System Atrophy; Parkinson Disease; Phosphorylation; Pure Autonomic Failure; Synaptic Transmission; Ubiquitinated Proteins; Ubiquitination

Changes in protein metabolism are key to disease onset and progression in many neurodegenerative diseases. As a prime example, in Parkinson's disease, folding, post-translational modification and recycling of the synaptic protein α-synuclein are clearly altered, leading to a progressive accumulation of pathogenic protein species and the formation of intracellular inclusion bodies. Altered protein folding is one of the first steps of an increasingly understood cascade in which α-synuclein forms complex oligomers and finally distinct protein aggregates, termed Lewy bodies and Lewy neurites. In neurons, an elaborated network of chaperone and co-chaperone proteins is instrumental in mediating protein folding and re-folding. In addition to their direct influence on client proteins, chaperones interact with protein degradation pathways such as the ubiquitin-proteasome-system or autophagy in order to ensure the effective removal of irreversibly misfolded and potentially pathogenic proteins. Because of the vital role of proper protein folding for protein homeostasis, a growing number of studies have evaluated the contribution of chaperone proteins to neurodegeneration. We herein review our current understanding of the involvement of chaperones, co-chaperones and chaperone-mediated autophagy in synucleinopathies with a focus on the Hsp90 and Hsp70 chaperone system. We discuss genetic and pathological studies in Parkinson's disease as well as experimental studies in models of synucleinopathies that explore molecular chaperones and protein degradation pathways as a novel therapeutic target. To this end, we examine the capacity of chaperones to prevent or modulate neurodegeneration and summarize the current progress in models of Parkinson's disease and related neurodegenerative disorders.

Topics: alpha-Synuclein; Animals; Humans; Molecular Chaperones; Neurodegenerative Diseases; Parkinson Disease; Protein Folding

The "proteinopathy" hypothesis, which states that pathological inclusions result in neuronal death, is classically invoked to explain neurodegeneration. In this review on α-synuclein (αS), attention is shifted to the distal axons, where αS deposits earlier than in the cytoplasmic formation of Lewy bodies (LBs). Because LBs are preferentially formed in axons with abundant branching, hyperbranching may accentuate axonal degeneration and αS deposition in their distal ends. This hyperbranching may also explain why motor/non-motor symptoms of Parkinson disease (PD) are so generalized and diffuse with barely any localizing value. Such underlying structure templates both the distal-dominant degeneration with αS deposition, and the non-localizing nature of clinical manifestations of PD, and as such can be considered a "structural template" thereof. The evolution of PD symptoms can be highly variable, ranging from restricted LB lesions and corresponding, long-lived, symptoms (pure autonomic failure, cardiac denervation, essential tremor, and REM-related behavioral disorders, which may be collectively called "focal LB disease") to the more haphazard appearance of dementia or anosmia without developing parkinsonism or brainstem lesions. This variability is better explained by the parallel involvement of multiple systems with hyperbranching axons rather than the stereotyped upward spread of LB in the brainstem. Awareness of presynaptic dysfunctions of these hyperbranching systems may enhance the sensitivity and specificity of clinical diagnoses of PD for earlier therapeutic intervention.

Topics: alpha-Synuclein; Animals; Axons; Humans; Lewy Bodies; Lewy Body Disease; Parkinson Disease; Protein Transport

Parkinson's disease patients exhibit progressive spreading of aggregated α-synuclein in the nervous system. This slow process follows a specific pattern in an inflamed tissue environment. Recent research suggests that prion-like mechanisms contribute to the propagation of α-synuclein pathology. Little is known about factors that might affect the prion-like behavior of misfolded α-synuclein. In this review, we suggest that neuroinflammation plays an important role. We discuss causes of inflammation in the olfactory bulb and gastrointestinal tract and how this may promote the initial misfolding and aggregation of α-synuclein, which might set in motion events that lead to Parkinson's disease neuropathology. We propose that neuroinflammation promotes the prion-like behavior of α-synuclein and that novel anti-inflammatory therapies targeting this mechanism could slow disease progression.

Topics: alpha-Synuclein; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Communication; Humans; Inflammation; Olfactory Bulb; Parkinson Disease; Prions

The histopathological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is a major constituent. Pale bodies, the precursors of LBs, may serve the material for that LBs continue to expand. LBs consist of a heterogeneous mixture of more than 90 molecules, including PD-linked gene products (α-synuclein, DJ-1, LRRK2, parkin, and PINK-1), mitochondria-related proteins, and molecules implicated in the ubiquitin-proteasome system, autophagy, and aggresome formation. LB formation has been considered to be a marker for neuronal degeneration because neuronal loss is found in the predilection sites for LBs. However, recent studies have indicated that nonfibrillar α-synuclein is cytotoxic and that fibrillar aggregates of α-synuclein (LBs and pale bodies) may represent a cytoprotective mechanism in PD.

Topics: alpha-Synuclein; Animals; Humans; Lewy Bodies; Lewy Body Disease; Neurodegenerative Diseases; Parkinson Disease

Over the last two decades, significant strides has been made toward acquiring a better knowledge of both the etiology and pathogenesis of Parkinson's disease (PD). Experimental models are of paramount importance to obtain greater insights into the pathogenesis of the disease. Thus far, neurotoxin-based animal models have been the most popular tools employed to produce selective neuronal death in both in vitro and in vivo systems. These models have been commonly referred to as the pathogenic models. The current trend in modeling PD revolves around what can be called the disease gene-based models or etiologic models. The value of utilizing multiple models with a different mechanism of insult rests on the premise that dopamine-producing neurons die by stereotyped cascades that can be activated by a range of insults, from neurotoxins to downregulation and overexpression of disease-related genes. In this position article, we present the relevance of both pathogenic and etiologic models as well as the concept of clinically relevant designs that, we argue, should be utilized in the preclinical development phase of new neuroprotective therapies before embarking into clinical trials.

Topics: alpha-Synuclein; Animals; Disease Models, Animal; Genetic Vectors; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mice; Mice, Transgenic; Mutation; Neuroprotective Agents; Neurotoxins; Parkinson Disease; Protein Serine-Threonine Kinases

Parkinson's disease (PD), the second most common neurodegenerative disorder, affects 1-2 % of humans aged 60 years and older. The diagnosis of PD is based on motor symptoms such as bradykinesia, rigidity, tremor, and postural instability associated with the striatal dopaminergic deficit that is linked to neurodegenerative processes in the substantia nigra (SN). In the past, cellular replacement strategies have been evaluated for their potential to alleviate these symptoms. Adult neurogenesis, the generation of new neurons within two proliferative niches in the adult brain, is being intensively studied as one potential mode for cell-based therapies. The subventricular zone provides new neurons for the olfactory bulb functionally contributing to olfaction. The subgranular zone of the hippocampus produces new granule neurons for the dentate gyrus, required for memory formation and proper processing of anxiety provoking stimuli. Recent years have revealed that PD is associated with non-motor symptoms such as hyposmia, anhedonia, lack of novelty seeking behavior, depression, and anxiety that are not directly associated with neurodegenerative processes in the SN. This broad spectrum of non-motor symptoms may partly rely on proper olfactorial processing and hippocampal function. Therefore, it is conceivable that some non-motor deficits in PD are related to defective adult neurogenesis. Accordingly, in animal models and postmortem studies of PD, adult neurogenesis is severely affected, although the exact mechanisms and effects of these changes are not yet fully understood or are under debate due to conflicting results. Here, we review the current concepts related to the dynamic interplay between endogenous cellular plasticity and PD-associated pathology.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; alpha-Synuclein; Animals; Disease Models, Animal; Hippocampus; Humans; Neurogenesis; Olfactory Bulb; Parkinson Disease

Although there have been significant advances, pathogenesis in Parkinson's disease (PD) is still poorly understood. Potential clues about pathogenesis that have not been systematically pursued are suggested by the restricted pattern of neuronal pathology in the disease. In addition to dopaminergic neurons in the substantia nigra pars compacta (SNc), a significant number of other central and peripheral neuronal populations exhibit Lewy pathology (LP), phenotypic dysregulation, or frank degeneration in PD patients. Drawing on this literature, there appear to be a small number of risk factors contributing to vulnerability. These include autonomous activity, broad action potentials, low intrinsic calcium-buffering capacity, poorly myelinated long highly branched axons and terminal fields, and use of a monoamine neurotransmitter, often with the catecholamine-derived neuromelanin pigment. Of these phenotypic traits, only the physiological ones appear to provide a reachable therapeutic target at present.

Topics: alpha-Synuclein; Humans; Nerve Degeneration; Nervous System; Neurons; Parkinson Disease

Cardiovascular autonomic failure is the second most common dysautonomic feature of α-synucleinopathies and has significant impact on daily activities and quality of life. Here we provide a systematic review of cardiovascular autonomic failure in α-synucleinopathies, emphasizing its impact on cognitive functions and disease outcomes. Articles spanning the period between January 1985 and April 2012 were identified from the PubMed database using a keyword-based search. Epidemiological studies highlight the negative prognostic effect of cardiovascular autonomic failure on cardiovascular and cerebrovascular outcomes and overall mortality in all α-synucleinopathies. Altered cerebral perfusion, vascular pressure stress, and related disruption of the blood-brain barrier may also contribute to the white matter hyperintensities and cognitive dysfunction frequently found in patients affected by neurocardiovascular instability. These findings support the hypothesis that cardiovascular autonomic failure may play a negative prognostic role in α-synucleinopathies and suggest that precocious screening and therapeutic management of cardiovascular autonomic failure may positively impact disease course.

Topics: alpha-Synuclein; Brain; Cardiovascular System; Cognition Disorders; Disease Progression; Fatigue; Humans; Hypotension, Orthostatic; Lewy Body Disease; Multiple System Atrophy; Neurodegenerative Diseases; Parkinson Disease; Primary Dysautonomias; Prognosis; Pure Autonomic Failure

The toxicity of α-synuclein in the neuropathology of Parkinson's disease which includes its hallmark aggregation has been studied scrupulously in the last decade. Although little is known regarding the normal functions of α-synuclein, its association with membrane phospholipids suggests its potential role in signaling pathways. Following extensive evidences for its nuclear localization, we and others recently demonstrated DNA binding activity of α-synuclein that modulates its conformation as well as aggregation properties. Furthermore, we also underscored the similarities among various amyloidogenic proteins involved in neurodegenerative diseases including amyloid beta peptides and tau. Our more recent studies show that α-synuclein is glycated and glycosylated both in vitro and in neurons, significantly affecting its folding, oligomeric, and DNA binding properties. Glycated α-synuclein causes increased genome damage both via its direct interaction with DNA and by increased generation of reactive oxygen species as glycation byproduct. In this review, we discuss the mechanisms of glycation and other posttranslational modifications of α-synuclein, including phosphorylation and nitration, and their role in neuronal death in Parkinson's disease.

Topics: alpha-Synuclein; Animals; Cell Death; Glycation End Products, Advanced; Glycosylation; Humans; Parkinson Disease; Phosphorylation; Protein Binding; Protein Folding

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting ~1 % of people over the age of 65. Neuropathological hallmarks of PD are prominent loss of dopaminergic (DA) neurons in the substantia nigra and formation of intraneuronal protein inclusions termed Lewy bodies, composed mainly of α-synuclein (αSyn). Missense mutations in αSyn gene giving rise to production of degradation-resistant mutant proteins or multiplication of wild-type αSyn gene allele can cause rare inherited forms of PD. Therefore, the existence of abnormally high amount of αSyn protein is considered responsible for the DA neuronal death in PD. Normally, αSyn protein localizes to presynaptic terminals of neuronal cells, regulating the neurotransmitter release through the modulation of assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex. On the other hand, of note, pathological examinations on the recipient patients of fetal nigral transplants provided a prion-like cell-to-cell transmission hypothesis for abnormal αSyn. The extracellular αSyn fibrils can internalize to the cells and enhance intracellular formation of protein inclusions, thereby reducing cell viability. These findings suggest that effective removal of abnormal species of αSyn in the extracellular space as well as intracellular compartments can be of therapeutic relevance. In this review, we will focus on αSyn-triggered neuronal cell death and provide possible disease-modifying therapies targeting abnormally accumulating αSyn.

Topics: alpha-Synuclein; Animals; Cell Death; Cell Survival; Humans; Neurons; Parkinson Disease; Protein Transport

An increasing wealth of data indicates a close relationship between the presynaptic protein alpha-synuclein and Parkinson's disease (PD) pathogenesis. Alpha-synuclein protein levels are considered as a major determinant of its neurotoxic potential, whereas secreted extracellular alpha-synuclein has emerged as an additional important factor in this regard. However, the manner of alpha-synuclein degradation in neurons remains contentious. Both the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP)-mainly macroautophagy and chaperone-mediated autophagy-have been suggested to contribute to alpha-synuclein turnover. Additionally, other proteases such as calpains, neurosin, and metalloproteinases have been also proposed to have a role in intracellular and extracellular alpha-synuclein processing. Both UPS and ALP activity decline with aging and such decline may play a pivotal role in many neurodegenerative conditions. Alterations in these major proteolytic pathways may result in alpha-synuclein accumulation due to impaired clearance. Conversely, increased alpha-synuclein protein burden promotes the generation of aberrant species that may impair further UPS or ALP function, generating thus a bidirectional positive feedback loop leading to neuronal death. In the current review, we summarize the recent findings related to alpha-synuclein degradation, as well as to alpha-synuclein-mediated aberrant effects on protein degradation systems. Identifying the factors that regulate alpha-synuclein association to cellular proteolytic pathways may represent potential targets for therapeutic interventions in PD and related synucleinopathies.

Topics: alpha-Synuclein; Animals; Autophagy; Humans; Parkinson Disease; Proteolysis; Signal Transduction

Although resting tremor, cogwheel rigidity, hypokinesia/bradykinesia and postural instability usually dominate the clinical picture of sporadic Parkinson's disease (PD), both clinical and epidemiological data reveal that a wide variety of additional symptoms impair patients' quality of life considerably, parallel to the chronic progressive neurodegenerative movement disorder. Autopsy based retrospective studies have shown that α-synuclein immunoreactive Lewy pathology (LP) develops in the locus coeruleus (LC) of patients with neuropathologically confirmed sporadic PD, as well as in individuals with incidental (prodromal or premotor) Lewy body disease but not in age and gender matched controls. Using five case studies, this review discusses the possible role of LP (axonopathy, cellular dysfunction and nerve cell loss) in the LC, catecholaminergic tract and related circuitry in the development of PD-related dementia. The contribution of noradrenergic deficit to cognitive dysfunction in PD has been underappreciated. Noradrenergic therapeutic interventions might not only alleviate depressive symptoms and anxiety but also delay the onset of cognitive decline.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Atherosclerosis; Autopsy; Brain; Dementia; Disease Progression; Female; Humans; Lewy Body Disease; Locus Coeruleus; Male; Nerve Net; Norepinephrine; Parkinson Disease; REM Sleep Behavior Disorder; Sleep Initiation and Maintenance Disorders