Phosphorylated ?-synuclein in Parkinson's disease.
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ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC3302662 | biostudies-literature | 2012 Feb
REPOSITORIES: biostudies-literature
Publications
Phosphorylated α-synuclein in Parkinson's disease.
Wang Yu Y Shi Min M Chung Kathryn A KA Zabetian Cyrus P CP Leverenz James B JB Berg Daniela D Srulijes Karin K Trojanowski John Q JQ Lee Virginia M-Y VM Siderowf Andrew D AD Hurtig Howard H Litvan Irene I Schiess Mya C MC Peskind Elaine R ER Masuda Masami M Hasegawa Masato M Lin Xiangmin X Pan Catherine C Galasko Douglas D Goldstein David S DS Jensen Poul Henning PH Yang Hui H Cain Kevin C KC Zhang Jing J
Science translational medicine 20120201 121
Phosphorylated α-synuclein (PS-129), a protein implicated in the pathogenesis of Parkinson's disease (PD), was identified by mass spectrometry in human cerebrospinal fluid (CSF). A highly sensitive and specific assay was established and used to measure PS-129 together with total α-synuclein in the CSF of patients with PD, other parkinsonian disorders such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), and healthy individuals (a total of ~600 samples). PS-129 CSF conce ...[more]
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Project description:Parkinson's disease is the second most important neurodegenerative disorder worldwide. It is characterized by the presence of Lewy bodies, which are mainly composed of ?-synuclein and ubiquitin-bound proteins. Both the ubiquitin proteasome system (UPS) and autophagy-lysosomal pathway (ALS) are altered in Parkinson's disease, leading to aggregation of proteins, particularly ?-synuclein. Interestingly, it has been observed that copper promotes the protein aggregation process. Additionally, phosphorylation of ?-synuclein along with copper also affects the protein aggregation process. The interrelation among ?-synuclein phosphorylation and its capability to interact with copper, with the subsequent disruption of the protein degradation systems in the neurodegenerative process of Parkinson's disease, will be analyzed in detail in this review.
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Project description:BackgroundDespite decades of intensive research, to date, there is no accepted diagnosis for Parkinson's disease (PD) based on biochemical analysis of blood or CSF. However, neurodegeneration in the brains of PD patients begins several years before the manifestation of the clinical symptoms, pointing to serious flaw/limitations in this approach.ResultsTo explore the potential use of alpha-synuclein (?-syn) species as candidate biomarkers for PD, we generated specific antibodies directed against wide array of ?-syn species, namely total-, oligomeric- and phosphorylated-Ser129-?-syn (t-, o- and p-S129-?-syn). Next we sought to employ our antibodies to develop highly specific ELISA assays to quantify ?-syn species in biological samples. Finally we verified the usefulness of our assays in CSF samples from 46 PD patients and 48 age-matched healthy controls. We also assessed the discriminating power of combining multiple CSF ?-syn species with classical Alzheimer's disease biomarkers. The combination of CSF o-/t-?-syn, p-S129-?-syn and p-tau provided the best fitting predictive model for discriminating PD patients from controls. Moreover, CSF o-?-syn levels correlated significantly with the severity of PD motor symptoms (r?=?-0.37).ConclusionOur new ELISA assays can serve as research tools to address the unmet need for reliable CSF biomarkers for PD and related disorders.
| S-EPMC4717559 | biostudies-literature
Project description:Serine 129-phosphorylated alpha-synuclein (pS-α-syn) is a major form of α-syn relevant to the pathogenesis of Parkinson's disease (PD), which has been recently detected in red blood cells (RBCs). However, alterations of RBC-derived pS-α-syn (pS-α-syn-RBC) in different subtypes and stages of PD remains to be investigated. In the present study, by using enzyme-linked immunosorbent assay (ELISA) to measure pS-α-syn-RBC, we demonstrated significantly higher levels of pS-α-syn-RBC in PD patients than in healthy controls. pS-α-syn-RBC separated the patients well from the controls, with a sensitivity of 93.39% (95% CI: 90.17-95.81%), a specificity of 93.11% (95% CI: 89.85-95.58%), and an area under the curve (AUC) of 0.96. Considering motor subtypes, the levels of pS-α-syn-RBC were significantly higher in late-onset than young-onset PD (p = 0.013) and in those with postural instability and gait difficulty than with tremor-dominant (TD) phenotype (p = 0.029). In addition, the levels of pS-α-syn-RBC were also different in non-motor subtypes, which were significantly lower in patients with cognitive impairment (p = 0.012) and olfactory loss (p = 0.004) than in those without such symptoms. Moreover, the levels of pS-α-syn-RBC in PD patients were positively correlated with disease duration and Hoehn & Yahr stages (H&Y) (p for trend =0.02 and <0.001) as well as UPDRS III (R 2 = 0.031, p = 0.0042) and MoCA scores (R 2 = 0.048, p = 0.0004). The results obtained suggest that pS-α-syn-RBC can be used as a potential biomarker for not only separating PD patients from healthy controls but also predicting the subtypes and stages of PD.
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2015-06-01 | GSE57475 | GEO
Project description:Whole gene duplications and triplications of alpha-synuclein (SNCA) can cause Parkinson's disease (PD), and variation in the promoter region (Rep1) and 3' region of SNCA has been reported to increase disease susceptibility. Within our cohort, one affected individual from each of 92 multiplex PD families showing the greatest evidence of linkage to the region around SNCA was screened for dosage alterations and sequence changes; no dosage or non-synonymous sequence changes were found. In addition, 737 individuals (from 450 multiplex PD families) that met strict diagnostic criteria for PD and did not harbor a known causative mutation, as well as 359 neurologically normal controls, were genotyped for the Rep1 polymorphism and four SNPs in the 3' region of SNCA. The four SNPs were in high LD (r(2) > 0.95) and were analyzed as a haplotype. The effects of the Rep1 genotype and the 3' haplotype were evaluated using regression models employing only one individual per family. Cases had a 3% higher frequency of the Rep1 263 bp allele compared with controls (OR = 1.54; empirical P-value = 0.02). There was an inverse linear relationship between the number of 263 bp alleles and age of onset (empirical P-value = 0.0004). The 3' haplotype was also associated with disease (OR = 1.29; empirical P-value = 0.01), but not age of onset (P = 0.40). These data suggest that dosage and sequence changes are a rare cause of PD, but variation in the promoter and 3' region of SNCA convey an increased risk for PD.
| S-EPMC3397145 | biostudies-literature
Project description:Parkinson's disease (PD), a neurodegenerative disorder characterized by distinct aging-independent loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) region urging toward neuronal loss. Over the decade, various key findings from clinical perspective to molecular pathogenesis have aided in understanding the genetics with assorted genes related with PD. Subsequently, several pathways have been incriminated in the pathogenesis of PD, involving mitochondrial dysfunction, protein aggregation, and misfolding. On the other hand, the sporadic form of PD cases is found with no genetic linkage, which still remain an unanswered question? The exertion in ascertaining vulnerability factors in PD considering the genetic factors are to be further dissevered in the forthcoming decades with advancement in research studies. One of the major proponents behind the prognosis of PD is the pathogenic transmutation of aberrant alpha-synuclein protein into amyloid fibrillar structures, which actuates neurodegeneration. Alpha-synuclein, transcribed by SNCA gene is a neuroprotein found predominantly in brain. It is implicated in the modulation of synaptic vesicle transport and eventual release of neurotransmitters. Due to genetic mutations and other elusive factors, the alpha-synuclein misfolds into its amyloid form. Therefore, this review aims in briefing the molecular understanding of the alpha-synuclein associated with PD.
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Project description:OBJECTIVE:To test the hypothesis that variability in SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the gene encoding ?-synuclein, modifies the association between head injury and Parkinson's disease (PD) risk. METHODS:Participants in the Farming and Movement Evaluation (FAME) and the Study of Environmental Association and Risk of Parkinsonism using Case-Control Historical Interviews (SEARCH), 2 independent case-control studies, were genotyped for Rep1 and interviewed regarding head injuries with loss of consciousness or concussion prior to Parkinson's disease (PD) diagnosis. Logistic regression modeling adjusted for potential confounding variables and tested interaction between Rep1 genotype and head injury. RESULTS:Consistent with prior reports, relative to medium-length Rep1, short Rep1 genotype was associated with reduced PD risk (pooled odds ratio [OR], 0.7; 95% confidence interval [CI], 0.5-0.9), and long Rep1 with increased risk (pooled OR, 1.4; 95% CI, 0.95-2.2). Overall, head injury was not significantly associated with PD (pooled OR, 1.3; 95% CI, 0.9-1.8). However, head injury was strongly associated with PD in those with long Rep1 (FAME OR, 5.4; 95% CI, 1.5-19; SEARCH OR, 2.3; 95% CI, 0.6-9.2; pooled OR, 3.5; 95% CI 1.4-9.2, p-interaction = 0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p = 0.03). INTERPRETATION:While head injury alone was not associated with PD risk, our data suggest head injury may initiate and/or accelerate neurodegeneration when levels of synuclein are high, as in those with Rep1 expansion. Given the high population frequency of head injury, independent verification of these results is essential.
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Project description:Background: Parkinson's disease (PD) is characterized by proteinopathies and these proteinopathies seem to interact synergistically and lead to protein aggregations and changes in protein cerebrospinal fluid (CSF) levels. In this study, we aimed to explore the longitudinal changes of CSF a lpha-synuclein (?-syn), total tau (t-tau), phosphorylated tau (p-tau), and beta-amyloid (A?1-42) and their relationships with each other and with baseline clinical entities like REM sleep behavior disorder (RBD), cognitive impairment, motor symptoms, and olfaction dysfunction. Method: One hundred and twelve non-demented PD patients and 110 controls were recruited from Parkinson's Progression Markers Initiative (PPMI).We used a linear mixed model within groups to assess longitudinal protein changes over 6 and 12 months and a random regression coefficient within the linear mixed model to investigate the correlation between proteins and their baseline clinical characteristics. Results: P-tau was lower in PDs only at baseline, but during a year, p-tau increased more rapidly in PDs than controls. A?1-42 was not significantly different between groups at any separate timepoint; however, when assessed longitudinally, A?1-42 showed significant changes in both groups. Conversely, t-tau and ?-syn differed significantly between groups, but their longitudinal changes were not significant in either of the groups. Moreover, all proteins' baseline levels, except p-tau, could determine estimated longitudinal tau changes. Baseline RBDSQ scores but not UPDRS III, MoCA, or UPSIT scores were predictive of longitudinal increase in ?-syn levels. Conclusion: Longitudinal changes in levels of CSF proteins are related to each other and could help researchers further understand PD pathology. In addition, RBD seems to be a potential prognostic factor for PD progression. However, in order to reach a consensus, longer follow-up times are required.
| S-EPMC6052894 | biostudies-literature
Project description:Parkinson's disease (PD) is a common human neurodegenerative movement disorder. Studies of the genetic forms of PD have helped to reveal disease mechanisms. Functional interactions between some Parkinson's disease (PD) genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1 and alpha-synuclein, a protein with a key role in the pathogenesis of both sporadic and familial PD. We extend our findings from yeast to an animal model and show these interactions are conserved in neurons. We also connect VPS35 impairments to neurodegeneration in alpha-synuclein transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to alpha-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future genetic and functional interrogation. Ribosome profiling (RiboSeq) of wild type and VPS35 deletion yeast strains, with or without overexpression of the TIF4631 initiation factor
2014-12-19 | E-GEOD-64304 | biostudies-arrayexpress
Project description: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.
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