alpha-synuclein and Chronic-Disease

Epidemiological studies show correlations between constipation and development of Parkinson's disease (PD); however, few studies have explored the association between constipation and dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and multiple system atrophy (MSA). We sought to explore the lifelong association of constipation and PD, DLB, PDD, and MSA (α-Synucleinopathies), compared to age- and sex-matched controls.. Using the Rochester Epidemiology Project (REP), we established an incident cohort of clinically defined α-synucleinopathies. A movement-disorder specialist reviewed all medical charts to establish clinical diagnoses.. We identified 453 incident cases of clinically diagnosed α-synucleinopathies and an identical number of age- and sex-matched controls in Olmsted County (MN), 1991-2010. There were 303 cases of PD; 80, DLB; 54, PDD; and 16, MSA. Approximately 50% of α-synucleinopathies of all types reported constipation, compared to 27% in controls. The earliest pre-motor onset constipation was in DLB (median, 3.76 years prior to α-synucleinopathies motor-symptom onset); latest onset post-motor constipation was in PD (median, 5.15 years after motor-symptom onset). PD also had the highest longstanding constipation rate (18.2%). All α-synucleinopathies had higher odds of constipation compared to controls, except for MSA (p = 0.09), likely due to a limited sample size.. PD, DLB, and PDD had higher odds of constipation compared to controls; PD had the most widespread onset of lifelong constipation, both longstanding and pre- or post-motor onset symptoms. Our results indicate that constipation rates do not differ among α-synucleinopathies but do differ in terms of temporal onset compared to disease onset.

Topics: alpha-Synuclein; Chronic Disease; Constipation; Dementia; Humans; Lewy Body Disease; Minnesota; Multiple System Atrophy; Parkinson Disease; Synucleinopathies

Introduction: Excessive alcohol consumption results in neuroadaptation, neurodegeneration, and differential expression of numerous genes.\ Objective: To determine the relationship between the expression of the alpha synuclein gene (SNCA) in blood, single nucleotide variant (SNV) in its promoter region, and chronic constipation in people with problems of alcohol consumption.\ Materials and methods: The sample consisted of 35 controls and 27 cases selected according to the score obtained with the AUDIT tool. For the diagnosis of constipation, the Rome IV criteria were applied. Nucleic acid extraction was performed from peripheral blood and the expression of the gene was evaluated by qPCR, protein quantification by ELISA, and the presence of SNV in the promoter region of the gene by Sanger sequencing.\ Results: We observed a relative gene overexpression of SNCA mRNA in the case group, which was not related to the diagnosis of chronic constipation. There was 4.8 times greater risk of presenting constipation in the group of cases. Besides, nine single nucleotide variants were found in a segment of the promoter region of the gene rich in CpG regulatory sequences with similar frequency between the groups while a variant was identified in position -2171, which is not reported in GenBank for variants and whose genotype A/T was associated with increased expression of SNCA mRNA.\ Conclusion: We evidenced an overexpression of alpha synuclein mRNA in people with problems of alcohol consumption that was not related to the diagnosis of chronic constipation.. Introducción. El consumo excesivo de alcohol resulta en neuroadaptación, neurodegeneración y expresión diferencial de numerosos genes. Objetivo. Determinar la relación entre la expresión del gen de la alfa sinucleína (SNCA) en sangre, las variantes de nucleótido único (Single Nucleotide Variant, SNV) en su región promotora y el estreñimiento crónico en personas con problemas de consumo de alcohol. Materiales y métodos. La muestra estuvo conformada por 35 controles y 27 casos, seleccionados según el puntaje obtenido con la herramienta AUDIT. En el diagnóstico del estreñimiento se aplicaron los criterios de Roma IV. La extracción de ácidos nucleicos se hizo a partir de sangre periférica y se evaluó la expresión del gen mediante qPCR, la cuantificación proteica por ELISA y la presencia de SNV en la región promotora del gen por la secuenciación de Sanger. Resultados. Se observó sobreexpresión génica relativa de ARNm del gen SNCA en el grupo de casos sin relación con el estreñimiento crónico. Se evidenció un riesgo 4,8 veces mayor de presentar estreñimiento en el grupo de casos. Se encontraron nueve variantes de nucleótido simple en un segmento de la región promotora del gen rica en secuencias reguladoras CpG, con frecuencia similar entre los grupos, y se detectó una variante en la posición -2171 que no se encuentra reportada en GenBank para variantes clínicas y cuyo genotipo A/T se relacionó con el incremento de la expresión del ARNm del SNCA. Conclusión. En personas con problemas de consumo de alcohol se evidenció la sobreexpresión del ARNm de alfa sinucleína, lo cual no se relacionó con el diagnóstico de estreñimiento crónico.

Topics: Adult; Alcoholism; alpha-Synuclein; Case-Control Studies; Chronic Disease; Colombia; Constipation; Female; Gastrointestinal Motility; Gene Expression; Gene Frequency; Humans; Inflammation; Leukocytes, Mononuclear; Male; Polymorphism, Single Nucleotide; Prevalence; Promoter Regions, Genetic; RNA, Messenger; Urban Population; Young Adult

Parkinson's disease (PD), a progressive neurodegenerative disease, is caused by the loss of dopaminergic neurons in the substantia nigra (SN). It is characterized by the formation of intracytoplasmic Lewy bodies that are primarily composed of the protein alpha-synuclein (

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Acupuncture Therapy; alpha-Synuclein; Animals; Chronic Disease; Corpus Striatum; Disease Models, Animal; Gene Expression; Immediate-Early Proteins; Immunohistochemistry; Male; Mice, Inbred C57BL; Parkinsonian Disorders; Protein Serine-Threonine Kinases; Substantia Nigra

Neuroinflammation mediated by chronically activated microglia, largely caused by abnormal accumulation of misfolded α-synuclein (αSyn) protein, is known to contribute to the pathophysiology of Parkinson's disease (PD). In this work, based on the immunomodulatory activities displayed by particular heat-shock proteins (HSPs), we tested a novel vaccination strategy that used a combination of αSyn and Grp94 (HSPC4 or Gp96) chaperone and a murine PD model. We used two different procedures, first, the adoptive transfer of splenocytes from αSyn/Grp94-immunized mice to recipient animals, and second, direct immunization with αSyn/Grp94, to study the effects in a chronic mouse MPTP-model of parkinsonism. We found that both approaches promoted a distinct profile in the peripheral system-supported by humoral and cellular immunity-consisting of a Th1-shifted αSyn-specific response accompanied by an immune-regulatory/Th2-skewed general phenotype. Remarkably, this mixed profile sustained by αSyn/Grp94 immunization led to strong suppression of microglial activation in the substantia nigra and striatum, pointing to a newly described positive effect of anti-αSyn Th1-responses in the context of PD. This strategy is the first to target αSyn and report the suppression of PD-associated microgliosis. Overall, we show that the αSyn/Grp94 combination supports a distinct and long-lasting immune profile in the peripheral system, which has an impact at the CNS level by suppressing chronic microglial activation in an MPTP model of PD. Furthermore, our study demonstrates that reshaping peripheral immunity by vaccination with appropriate misfolding protein/HSP combinations could be highly beneficial as a treatment for neurodegenerative misfolding diseases.

Topics: Adoptive Transfer; alpha-Synuclein; Analysis of Variance; Animals; CD4 Antigens; Chronic Disease; Cytokines; Disease Models, Animal; Gliosis; Immunization; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Microglia; MPTP Poisoning; Substantia Nigra; T-Lymphocytes, Regulatory

Lewy body forms of primary chronic autonomic failure (CAF) such as incidental Lewy body disease (ILBD), Parkinson's disease (PD), and pure autonomic failure evolving into dementia with Lewy bodies (PAF+DLB) feature cardiac sympathetic denervation, whereas multiple system atrophy (MSA) in most cases does not. What links Lewy bodies with cardiac sympathetic denervation in CAF? In familial PD, abnormalities of the alpha-synuclein (AS) gene cause CAF and cardiac sympathetic denervation; and in sporadic PD, brainstem Lewy bodies contain AS co-localized with tyrosine hydroxylase (TH), a marker of catecholaminergic neurons. Cytotoxicity from AS deposition within sympathetic neurons might explain noradrenergic denervation in Lewy body forms of CAF. We used immunofluorescence microscopy (IM) to explore this possibility in sympathetic ganglia obtained at autopsy from CAF patients.. Immunoreactive AS and TH were imaged in sympathetic ganglion tissue from 6 control subjects (2 with ILBD), 5 PD patients (1 with concurrent PSP), and 3 patients with CAF (2 PAF + DLB, 1 MSA).. MSA involved normal ganglionic TH and no AS deposition. In ILBD TH was variably decreased, and TH and AS were co-localized in Lewy bodies. In PD TH was substantially decreased, and TH and AS were co-localized in Lewy bodies. In PAF + DLB TH was virtually absent, but AS was present in Lewy bodies. The PD + PSP patient had AS co-localized with tau but not TH.. Sympathetic denervation and intraneuronal AS deposition are correlated across CAF syndromes, consistent with a pathogenic contribution of synucleinopathy to cardiac noradrenergic deficiency in Lewy body diseases.

Topics: alpha-Synuclein; Chronic Disease; Ganglia, Sympathetic; Humans; Lewy Body Disease; Parkinson Disease; Pure Autonomic Failure; Tyrosine 3-Monooxygenase

Parkinson's disease (PD) is a chronically progressive neurodegenerative disease, with its main pathological hallmarks being a dramatic loss of dopaminergic neurons predominantly in the Substantia Nigra (SN), and the formations of intracytoplasmic Lewy bodies and dystrophic neurites. Alpha-synuclein (α-syn), widely recognized as the most prominent element of the Lewy body, is one of the representative hallmarks in PD. However, the mechanisms behind the increased α-syn expression and aggregation have not yet been clarified. To examine what causes α-syn expression to increase, we analyzed the pattern of gene expression in the SN of mice intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), where down-regulation of dopaminergic cells occurred. We identified serum- and glucocorticoid-dependent kinase 1 (SGK1) as one of the genes that is evidently downregulated in chronic MPTP-intoxication. The results of Western blot analyses showed that, together with the down-regulation of dopaminergic cells, the decrease in SGK1 expression increased α-syn expression in the SN in a chronic MPTP-induced Parkinsonism mouse. For an examination of the expression correlation between SGK1 and α-syn, SH-5YSY cells were knocked down with SGK1 siRNA then, the downregulation of dopaminergic cells and the increase in the expression of α-syn were observed. These results suggest that decreased expression of SGK1 may play a critical role in increasing the expression of α-syn, which is related with dopaminergic cell death in the SN of chronic MPTP-induced Parkinsonism mice and in SH-SY5Y cells.

Topics: alpha-Synuclein; Animals; Cell Count; Cell Line; Chronic Disease; Disease Models, Animal; Dopaminergic Neurons; Down-Regulation; Humans; Immediate-Early Proteins; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning; Parkinson Disease, Secondary; Protein Serine-Threonine Kinases; Substantia Nigra

Accumulation of alpha-synuclein (α-Syn) is significantly correlated with the presence of progressive motor deficits, which is the main symptom of Parkinson's disease (PD). Although physical exercise reduces α-Syn levels, the molecular mechanisms by which physical exercise decreases α-Syn remain unclear. We hypothesized that treadmill exercise (TE) decreases α-Syn levels by improving mitochondrial function and promoting autophagy via the sirtuin-1 (SIRT1) signaling pathway in the chronic 1-methyl-1,2,3,6-tetrahydropyridine with probenecid (MPTP/P)-induced mouse model of PD. We found that TE reduces α-Syn levels, which subsequently ameliorates dopaminergic (DAergic) neuron loss and α-Syn-mediated apoptotic cell death. Most importantly, TE increases SIRT1 expression, which results in increased mitochondrial biogenesis and decreased oxidative stress by activating peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). SIRT1 activation by TE also promotes autophagic clearance of α-Syn by inducing the activation of microtubule-associated protein 1 light chain 3 (LC3). Collectively, our results demonstrate that TE may reduce α-Syn levels by improving mitochondrial function and increasing autophagic flux, thereby ameliorating chronic MPTP/P-induced motor deficits in PD mice.

Topics: alpha-Synuclein; Animals; Autophagy; Chronic Disease; Corpus Striatum; Dopaminergic Neurons; Exercise Therapy; Gene Expression; Male; Mice, Inbred C57BL; Mitochondria; Motor Skills; MPTP Poisoning; Pars Compacta; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Random Allocation; Running; Sirtuin 1

Type 2 diabetes mellitus (T2DM) is a risk factor for Parkinson's disease (PD). Therefore, treatment to improve insulin resistance in T2DM may be useful for PD patients. Glucose dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family that can promote insulin release and improve insulin resistance. Several GIP analogues have been developed as potential treatments for T2DM. We had shown previously that D-Ala2-GIP-glu-PAL, a novel long-acting GIP analogue, can play a neuroprotective role in the PD mouse model induced by acute MPTP injection. The drug reduced damage to the dopaminergic neurons and increased CREB-mediated Bcl-2 expression to prevent apoptosis and reduced chronic inflammation in the brain. In the present study, we further tested the effects of chronic treatment by D-Ala2-GIP-glu-PAL in a chronic PD mouse model induced by MPTP (25mg/kg ip.) combination with probenecid (250mg/kg ip.) injection for 5 weeks. The results demonstrated that chronic treatment with D-Ala2-GIP-glu-PAL inhibits MPTP -induced Parkinsonism-like motor disorders in mice, and that the drug prevents dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc). Moreover, D-Ala2-GIP-glu-PAL also inhibited the increased levels of expression of α-synuclein in the SNpc and striatum induced by MPTP. Furthermore, drug treatment reduced chronic neuroinflammation, oxidative stress and lipid peroxidation, and increased the expression of BDNF. These findings show that GIP signaling is neuroprotective and holds promise as a novel treatment of PD.

Topics: alpha-Synuclein; Animals; Astrocytes; Brain-Derived Neurotrophic Factor; Cell Count; Chronic Disease; Disease Models, Animal; Dopaminergic Neurons; Gastric Inhibitory Polypeptide; Gene Expression Regulation; Inflammation; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Microglia; Motor Activity; Neostriatum; Parkinson Disease; Pars Compacta

Dan-zhi-xiao-yao-san is a Traditional Chinese Medicinal formulation widely used for the treatment of neuropsychological disorders. The present study examined the anxiolytic and neuroprotective effects of Dan-zhi-xiao-yao-san in a rat model of chronic stress. The results of an elevated plus maze test showed that Dan‑zhi‑xiao‑yao‑san significantly attenuated the levels of anxiety-induced stress as evidenced by increases in the time spent in the open arm region, as well as the percentage of entries into this area. In addition, Dan-zhi-xiao-yao-san alleviated stress‑induced neuronal death, as indicated by histological examination. Furthermore, mechanistic studies suggested that the anxiolytic and neuroprotective effects of Dan-zhi-xiao-yao-san may be mediated via attenuation of chronic stress‑induced upregulation of α‑synuclein and corticosterone, and downregulation of protein phosphatase 2A (PP2A) in the hippocampal region of the brain at the mRNA and protein level. In addition, Dan‑zhi‑xiao‑yao‑san decreased the serum levels of stress‑induced corticosterone in the model animals. In conclusion, the present study demonstrated that Dan‑zhi‑xiao‑yao‑san exerted anxiolytic and neuroprotective effects in a rat model of chronic stress via attenuation of stress‑induced upregulation of α‑synuclein and corticosterone, and downregulation of PP2A in the hippocampus.

Topics: alpha-Synuclein; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Brain; Chronic Disease; Disease Models, Animal; Drugs, Chinese Herbal; Female; Immunohistochemistry; Maze Learning; Neuroprotective Agents; Protein Phosphatase 2; Rats; Stress, Physiological; Stress, Psychological

The long-term consequences of traumatic brain injury (TBI) are closely associated with the development of histopathological deficits. Notably, TBI may predispose long-term survivors to age-related neurodegenerative diseases, such as Parkinson's disease (PD), which is characterized by a gradual degeneration of the nigrostriatal dopaminergic neurons. However, preclinical studies on the pathophysiological changes in substantia nigra (SN) after chronic TBI are lacking. In the present in vivo study, we examined the pathological link between PD-associated dopaminergic neuronal loss and chronic TBI. Sixty days post-TBI, rats were euthanized and brain tissues harvested. Immunostaining was performed using tyrosine hydroxylase (TH), an enzyme required for the synthesis of dopamine in neurons, α-synuclein, a presynaptic protein that plays a role in synaptic vesicle recycling, and major histocompatibility complex II (MHCII), a protein found in antigen presenting cells such as inflammatory microglia cells, all key players in PD pathology. Unbiased stereology analyses revealed significant decrease of TH-positive expression in the surviving dopaminergic neurons of the SN pars compacta (SNpc) relative to sham control. In parallel, increased α-synuclein accumulation was detected in the ipsilateral SN compared to the contralateral SN in TBI animals or sham control. In addition, exacerbation of MHCII+ cells was recognized in the SN and cerebral peduncle ipsilateral to injury relative to contralateral side and sham control. These results suggest α-synuclein as a pathological link between chronic effects of TBI and PD symptoms as evidenced by significant overexpression and abnormal accumulation of α-synuclein in inflammation-infiltrated SN of rats exposed to chronic TBI.

Topics: alpha-Synuclein; Animals; Brain Injuries; Cerebral Peduncle; Chronic Disease; Dopaminergic Neurons; Down-Regulation; Histocompatibility Antigens Class II; Microglia; Models, Biological; Parkinson Disease; Pars Compacta; Rats, Sprague-Dawley; Tyrosine 3-Monooxygenase; Up-Regulation

The overexpression of alpha-synuclein has been associated with neurodegenerative diseases, especially when the protein aggregates to form insoluble structures. The present study examined the effect of chronic hyperammonaemia on alpha-synuclein expression in the rat cerebellum following portacaval anastomosis (PCA).. Immunohistochemical and western blot determinations were performed 1 month and 6 months after the PCA procedure.. A time-dependent increase in alpha-synuclein expression was seen in the cerebellar grey matter compared with the controls. At 1 month post PCA, alpha-synuclein-immunopositive material was observed in the molecular layer, while the Purkinje cells showed weak alpha-synuclein expression, and alpha-synuclein aggregates were observed throughout the granular layer. At 6 months post PCA, alpha-synuclein expression was significantly increased compared with the controls. alpha-synuclein-immunostained astroglial cells were also found; the Bergmann glial cells showed alpha-synuclein-positive processes in the molecular layer of PCA-exposed rats, and in the granular layer, perivascular astrocytes showed intense alpha-synuclein immunoreactivity, as indicated by colocalization of alpha-synuclein with glial fibrillary acidic protein (GFAP). In addition, ubiquitin-immunoreactive inclusions were present in PCA-exposed rats, although they did not colocalize with alpha-synuclein. Western blotting performed at 6 months post PCA showed a reduction in the level of soluble alpha-synuclein compared with 1 month post PCA and the controls; this reduction was concomitant with an increase in the insoluble form of alpha-synuclein.. Although the precise mechanism by which alpha-synuclein aggregates in PCA-treated rats remains unknown, the present data suggest an important role for this protein in the onset and progression of hepatic encephalopathy, probably via its expression in astroglial cells.

Topics: alpha-Synuclein; Animals; Astrocytes; Blotting, Western; Cerebellum; Chronic Disease; Disease Models, Animal; Disease Progression; Hepatic Encephalopathy; Hyperammonemia; Immunohistochemistry; Male; Nerve Degeneration; Rats; Rats, Sprague-Dawley; Up-Regulation

Equine pituitary pars intermedia dysfunction (PPID) is a spontaneously occurring progressive disease affecting aged horses and ponies. The pathogenesis of PPID is poorly understood, but the available evidence supports a loss of dopaminergic inhibition of the melanotropes of the pars intermedia. Horses with PPID have increased plasma concentrations of pars intermedia pro-opiomelanocortin-derived peptides that decrease in response to dopamine or dopamine agonist administration. Dopamine and dopamine metabolite concentrations are decreased in the pars intermedia of affected horses compared to age-matched control horses. Horses with disease that are treated with the dopamine agonist pergolide show improvement in clinical signs and normalisation of diagnostic test results. In the present study, immunohistochemical evaluation of pituitary and hypothalamic tissue demonstrated reduced tyrosine hydroxylase immunoreactivity in affected horses compared to age-matched and young controls, supporting the role of dopaminergic neurodegeneration in PPID. In addition, immunohistochemical evaluation revealed an increase in the oxidative stress marker, 3-nitrotyrosine and in nerve terminal protein, alpha-synuclein that colocalised in the pars intermedia of horses with disease. These findings suggest a role for nitration of overexpressed alpha-synuclein in the pathogenesis of neurodegeneration in PPID.

Topics: alpha-Synuclein; Animals; Blotting, Western; Chronic Disease; Dopamine; Horse Diseases; Horses; Immunohistochemistry; Nerve Degeneration; Nerve Tissue Proteins; Nitrogen; Oxidative Stress; Pituitary ACTH Hypersecretion; Pituitary Gland; Synucleins; Tyrosine; Tyrosine 3-Monooxygenase

Direct protein interactions between the dopamine transporter and alpha-synuclein demonstrate that dopamine uptake function is modulated by alpha-synuclein. We report here that chronic cocaine abuse results in an increase in alpha-synuclein expression in the human striatum. Immunoblot analysis in the ventral putamen showed that alpha-synuclein protein was increased in striatal synaptosomes from cocaine users compared with age-matched drug-free controls. [H]-Dopamine transporter uptake was increased in parallel with 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane binding to the dopamine transporter. The increase in alpha-synuclein protein was more marked in the ventromedial sectors of the striatum than in the dorsal caudate nucleus. These results demonstrate concomitant regulation of alpha-synuclein and dopamine transporter binding and function in human striatal synaptic terminals isolated from cocaine abusers. Overexpression of alpha-synuclein may play a role in cocaine-induced plasticity and regulation of dopamine synaptic tone.

Topics: Adaptation, Physiological; alpha-Synuclein; Chronic Disease; Cocaine-Related Disorders; Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Homeostasis; Humans; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Presynaptic Terminals; Synucleins