alpha-synuclein and Tremor

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

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

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

Parkinson's disease (PD) is characterized by a gradual accumulation of neuropathology that may begin many years before a clinical diagnosis can be made using currently accepted criteria. Here, we first review the prevalence of α-synuclein neuropathology in elderly and discuss its clinical relevance in Parkinson patients. Subsequently, the results of a retrospective study focussing on the distribution of neuropathology in Parkinson patients with a tremor-dominant (TD), non-tremordominant (NTD) or rapid disease progression (RDP) subtype are presented. The study population recruited by the Netherlands Brain bank consisted of 149 non-neurological donors, 26 donors with incidental Lewy body disease (iLBD) and 111 Parkinson patients. In total, 89% of these cases could be classified in accordance with the Braak staging when taking into account the severity of α-synuclein pathology and adding an amygdala-predominant category of synucleinopathy. The pathological progression seemed to be non-linear. Interestingly, a strong correlation between neuronal loss and α-synuclein pathology was observed in the substantia nigra in Braak stages 3-6 (P < 0.01). However, there was no correlation between Hoehn & Yahr and Braak stages. Neuropathological progression may, however, vary between subtypes as cortical Lewy body load and Braak stages were higher in patients with NTD compared to TD and Alzheimer pathology was more prevalent in RDP patients. Recognition of clinical subtypes in neuropathological studies is essential to identify selective vulnerability to protein accumulation that may determine the clinical phenotype in PD.

Topics: alpha-Synuclein; Animals; Disease Progression; Humans; Incidental Findings; Parkinson Disease; Retrospective Studies; Tremor

Topics: Adolescent; Age of Onset; alpha-Synuclein; Child; Humans; Intracellular Signaling Peptides and Proteins; Oncogene Proteins; Parkinsonian Disorders; Protein Deglycase DJ-1; Protein Kinases; Receptors, Dopamine D5; Tremor; Ubiquitin-Protein Ligases

Recent molecular biology research on neurodegenerative diseases, including parkinsonisms, has identified mutations in the genes that code for the proteins alpha-synuclein and tau, which have been used to classify them into synucleinopathies and tauopathies. The synucleinopathies include, besides the most common and well studied Parkinson's disease (PD), dementia with Lewy bodies, which accounts for approximately 20% of all cases of dementia in the elderly, and multiple system atrophy, whereas the tauopathies include rare and rapidly progressive syndromes, such as progressive supranuclear palsy and corticobasal degeneration. Data we collected at our center in over 2900 parkinsonian patients show that PD accounts for no more than 70% of parkinsonisms. The various syndromes have many features in common that make the differential diagnosis difficult in the early stages of disease. Our data are consistent with the findings reported in the international literature and provide additional information useful for differential diagnosis.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Female; Humans; Hypokinesia; Lewy Bodies; Male; Middle Aged; Muscle Rigidity; Nerve Tissue Proteins; Neurons; Pain; Parkinsonian Disorders; Point Mutation; Postural Balance; Substantia Nigra; Synucleins; tau Proteins; Tremor

Protein misfolding within specific brain regions is a common characteristic of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease (PD). Therefore, a common term often used for these disorders is "proteinopathy". Currently, there has been increasing attention toward the overlap of pathogenesis between proteinopathies.. We aimed to explore the cross-sectional and longitudinal level of the CSF α-synuclein (α-syn), amyloid βeta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) in PD subjects with tremor dominant (TD) and a non-tremor dominant (nonTD) subtype from the Parkinson Progression Markers Initiative (PPMI).. We enrolled 411 early-stage PD patients and 187 healthy controls (HCs) from the PPMI. We compared the level of CSF biomarkers at four time points including baseline, 6 months, 1 year, and 2 years. To investigate longitudinal changes in CSF proteins within each group, we used linear mixed models.. The level of CSF biomarkers was significantly lower in PD patients compared to HCs at any visit. Moreover, there was no statistically significant difference in the level of CSF α-syn, Aβ1-42, t-tau, and p-tau between PD-TD and PD-nonTD. Longitudinal analysis showed significant CSF α-syn reduction after one year from baseline in PD-TD patients (P = 0.047). Also, there was a significant reduction in the level of CSF Aβ1-42 after two years in PD-nonTD patients but not HCs and PD-TD (P = 0.033).. Our results indicate that different patterns in longitudinal changes of CSF biomarkers could be due to different pathophysiological mechanisms involved in each PD motor subtype.

Topics: alpha-Synuclein; Amyloid beta-Peptides; Biomarkers; Cross-Sectional Studies; Humans; Parkinson Disease; Tremor

Parkinson's disease is one of the progressive neurodegenerative diseases from which people suffer for years. The mechanism of this disease is associated with a decrease in the number of dopaminergic neurons in the substantia nigra (SN) while Lewy bodies are still present. As a result, both motor-ridity, tremor, and bradykinesia-and non-motor symptoms such as anxiety and depression. Nowadays, it is well known that the cause behind Parkinson's disease is mainly environmental changes, genetic susceptibility, and toxins. Unfortunately, there is no cure for the disease but treatments. The replacement of lost neurons, α-synuclein and apomorphine, is currently being studied for new therapies. This article focuses on history, mechanism, factors causing Parkinson's disease as well as future therapies for the cure of the diseases.. Data were collected from medical journals published on PubMed, The Lancet, Cells, and Nature Reviews Neurology databases with a predefined search strategy. All articles considering new therapies for Parkinson's disease were considered.. The pathophysiology of Parkinson's disease is currently reasonably understood. However, there is no definitive cure so all the treatments focus mainly on reducing or limiting the symptoms. Current treatment studies focus on genetics, replacing lost neurons, α-synuclein and apomorphine.. Parkinson's disease is the most common movement disorder worldwide because of the loss of dopaminergic neurons in the substantia nigra. Its symptoms include motor dysfunctions such as rigidity, tremor, and bradykinesia and non-motor dysfunctions such as anxiety and depression. Through genetics, environmental changes and toxins analysis, it is now known that future new therapies are working on replacing lost neurons, α-synuclein and apomorphine.

Topics: alpha-Synuclein; Apomorphine; Dopaminergic Neurons; Humans; Hypokinesia; Parkinson Disease; Tremor

The extent of gait abnormality is non-uniform across motor phenotypes of Parkinson's disease (PD). The biological basis of this heterogeneity remains intriguing. Moreover, the relationship of gait impairment with various neurodegenerative protein markers in PD is not well established.. Here, we aimed to explore the interplay between gait parameters and specific serum protein markers in PD.. A total of 62 PD patients were consecutively recruited. Blood samples and gait data were acquired from 37 and 34 patients respectively. Two-dimensional spatio-temporal gait parameters were estimated using an electronic walkway (GAITRite®, CIR Systems Inc., USA). Serum phosphorylated alpha synuclein (p-Ser129-a-syn) and total a-syn levels were measured using commercially available ELISA kit. Data was analyzed using SPSS Version 20 (IBM).. We found that phosphorylated a-syn levels were significantly higher in PD patients with postural instability and gait difficulty compared to tremor dominant variant. Significant reduction in gait velocity was also observed with increasing levels of this pathological form of a-syn. Regression modelling showed that phosphorylated a-syn is an independent predictor of gait velocity.. Our findings indicate that concentrations of peripheral p-Ser129-a-syn but not total a-syn could be a potential contributor of gait impairment in PD. Further investigation on the systemic role of phosphorylated a-syn on gait would bridge the gap between central and peripheral mechanisms underlying phenotypic variability in PD.

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

Topics: alpha-Synuclein; Diagnosis, Differential; Hand; Humans; Male; Middle Aged; Neck Pain; Parkinson Disease; Tremor

The aim of our study is to examine the plasma levels of the four kinds of neurodegenerative proteins in plasma: α-syn, T-tau, P-tau

Topics: Aged; alpha-Synuclein; Amyloid beta-Peptides; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Gait; Humans; Linear Models; Male; Middle Aged; Motor Activity; Parkinson Disease; Peptide Fragments; Phosphorylation; Postural Balance; Severity of Illness Index; tau Proteins; Tremor

α-Synuclein and mutant huntingtin are the major constituents of the intracellular aggregates that characterize the pathology of Parkinson's disease (PD) and Huntington's disease (HD), respectively. α-Synuclein is likely to be a major contributor to PD, since overexpression of this protein resulting from genetic triplication is sufficient to cause human forms of PD. We have previously demonstrated that wild-type α-synuclein overexpression impairs macroautophagy in mammalian cells and in transgenic mice. Overexpression of human wild-type α-synuclein in cells and Drosophila models of HD worsens the disease phenotype. Here, we examined whether α-synuclein overexpression also worsens the HD phenotype in a mammalian system using two widely used N-terminal HD mouse models (R6/1 and N171-82Q). We also tested the effects of α-synuclein deletion in the same N-terminal HD mouse models, as well as assessed the effects of α-synuclein deletion on macroautophagy in mouse brains. We show that overexpression of wild-type α-synuclein in both mouse models of HD enhances the onset of tremors and has some influence on the rate of weight loss. On the other hand, α-synuclein deletion in both HD models increases autophagosome numbers and this is associated with a delayed onset of tremors and weight loss, two of the most prominent endophenotypes of the HD-like disease in mice. We have therefore established a functional link between these two aggregate-prone proteins in mammals and provide further support for the model that wild-type α-synuclein negatively regulates autophagy even at physiological levels.

Topics: Age of Onset; alpha-Synuclein; Animals; Brain; Disease Models, Animal; Disease Progression; Female; Gene Deletion; Humans; Huntingtin Protein; Huntington Disease; Intranuclear Inclusion Bodies; Male; Mice; Mice, Transgenic; Microtubule-Associated Proteins; Nerve Tissue Proteins; Nuclear Proteins; Tremor; Weight Loss

Rest tremor may occur in as many as 30% of essential tremor (ET) patients. It is not clear whether this tremor is a sentinel marker for brainstem Lewy body pathology. Here we report the clinical and post-mortem findings of nine ET cases with upper-extremity rest tremor in the absence of other parkinsonian features.. All brains had a complete neuropathological assessment. Tissue sections from the brainstem and basal ganglia were immunostained with α-synuclein antibody.. All cases had longstanding ET (median duration=42 years) with moderate to severe arm tremor. Rest tremor involved both arms in seven (77.8%) cases and one arm in two cases. The rest tremor score was correlated with the total action tremor score (r=0.69, p=0.04). The number of torpedoes was elevated, and Purkinje cells, reduced. Post-mortem changes in the substantia nigra pars compacta (SNc), caudate, putamen and globus pallidum were minimal, and neither Lewy bodies nor Lewy neurites were evident.. In nine ET brains with upper-extremity rest tremor, neither Lewy body-containing neurons nor Lewy neurites were found on α-synuclein immunostained sections, and other pathological changes in the basal ganglia were minimal. These data support the notion that isolated rest tremor in longstanding ET is not the expression of underlying Lewy body pathology in the SNc.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Basal Ganglia; Brain Stem; Caudate Nucleus; Essential Tremor; Female; Globus Pallidus; Humans; Lewy Bodies; Male; Middle Aged; Purkinje Cells; Putamen; Severity of Illness Index; Substantia Nigra; Tremor

Genetic classification of Parkinson's disease (PD) subtypes may become the preferred diagnostic tool for neurologists. Herein we compare clinical features from a large cohort of patients with familial PD of unknown aetiology or attributable to distinct genetic forms. Comprehensive neurological examinations were performed in 231 familial PD patients from Tunisia. Analysis was previously performed to screen for mutations in leucine rich repeat kinase 2 (LRRK2), PTEN induced kinase 1 (PINK1) and parkin (PRKN). Clinical features were compared between patients with genetically undefined PD (n=107) and those with LRRK2 (n=73) and PINK1 (n=42) mutations using regression analyses adjusted for gender, age of onset and disease duration. PRKN cases (n=9) were too few for meaningful statistical analysis. In comparison with genetically undefined patients, LRRK2 mutation carriers had more severe motor symptoms (median Unified Parkinson's Disease Rating Scale scores approximately 1.6 times higher, p<0.001), a higher rate of dyskinesia (OR 4.21, p=0.002) and use of dopamine agonists (OR 3.64, p<0.001), and less postural tremor (OR 0.21, p<0.001). PINK1 mutation carriers presented an increased rate of drug induced dyskinesia (OR 3.81, p=0.007) and a lower rate of postural tremor (OR 0.16, p<0.001) than genetically undefined patients. As expected, PINK1 patients had younger ages and ages at disease onset, and a longer disease duration compared with LRRK2 mutation carriers and genetically undefined patients. Clinical differences between LRRK2, PINK1 and genetically undefined familial PD appear more pronounced than previously appreciated, and may prove useful in clinical practice. As future therapies are targeted to specific protein abnormalities, identifying the genetic causes and associated clinical and pathological features will determine diagnosis, preventative medicine and drug intervention strategies.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Catchment Area, Health; Female; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Middle Aged; Parkinson Disease; Point Mutation; Prevalence; Protein Kinases; Protein Serine-Threonine Kinases; Tremor; Tunisia; Young Adult

Topics: alpha-Synuclein; Cognition Disorders; Female; Gene Duplication; Humans; Middle Aged; Neuropsychological Tests; Parkinson Disease; Posture; Severity of Illness Index; Tremor

We examined the clinical features of familial (n = 26) and sporadic (n = 52) Parkinson's disease (PD) in patients presenting over the age of 40 years. Familial PD cases were tested for alpha-synuclein or parkin mutations as appropriate. No mutations were found in any of the families investigated. We found no between-group differences in the age at onset of PD, the pattern or severity of parkinsonian features, the dose of antiparkinsonian medications or treatment related complications. Cases of familial and sporadic PD in our cohort of patients display similar clinical features. This may suggest similar etiologies for both familial and sporadic PD.

Topics: alpha-Synuclein; Antiparkinson Agents; Autonomic Nervous System Diseases; Cerebellar Ataxia; Chorea; Cohort Studies; Databases, Factual; Dementia; Disease Progression; Dystonia; Female; Humans; Ligases; Male; Middle Aged; Nerve Tissue Proteins; Paralysis; Parkinson Disease; Synucleins; Tremor; Ubiquitin-Protein Ligases