Alpha-synuclein mutations impair axonal regeneration in models of Parkinson's disease.
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ABSTRACT:
SUBMITTER: Tonges L
PROVIDER: S-EPMC4159996 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alpha-synuclein (SNCA) is crucial in the pathogenesis of Parkinson's disease (PD), yet mutations in the SNCA gene are rare. Evidence for somatic genetic variation in normal humans, also involving the brain, is increasing, but its role in disease is unknown. Somatic SNCA mutations, arising in early development and leading to mosaicism, could contribute to PD pathogenesis and yet be absent or undetectable in DNA derived from peripheral lymphocytes. Such mutations could underlie the widespread pathology in PD, with the precise clinical outcome dependent on their type and the timing and location of their occurrence. We recently reported a novel SNCA mutation (c.150T>G, p.H50Q) in PD brain-derived DNA. To determine if there was mosaicism for this, a PCR and cloning strategy was used to take advantage of a nearby heterozygous intronic polymorphism. No evidence of mosaicism was found. High-resolution melting curve analysis of SNCA coding exons, which was shown to be sensitive enough to detect low proportions of 2 known mutations, did not reveal any further mutations in DNA from 28 PD brain-derived samples. We outline the grounds that make the somatic SNCA mutation hypothesis consistent with genetic, embryological, and pathological data. Further studies of brain-derived DNA are warranted and should include DNA from multiple regions and methods for detecting other types of genomic variation.
| S-EPMC3739940 | biostudies-literature
Project description:Emerging evidence indicates that cellular senescence could be a critical inducing factor for aging-associated neurodegenerative disorders. However, the involvement of cellular senescence remains unclear in Parkinson's disease (PD). To determine this, we assessed the effects of α-synuclein preformed fibrils (α-syn PFF) or 1-methyl-4-phenylpyridinium (MPP+) on changes in cellular senescence markers, employing α-syn PFF treated-dopaminergic N27 cells, primary cortical neurons, astrocytes and microglia and α-syn PFF-injected mouse brain tissues, as well as human PD patient brains. Our results demonstrate that α-syn PFF-induced toxicity reduces the levels of Lamin B1 and HMGB1, both established markers of cellular senescence, in correlation with an increase in the levels of p21, a cell cycle-arrester and senescence marker, in both reactive astrocytes and microglia in mouse brains. Using Western blot and immunohistochemistry, we found these cellular senescence markers in reactive astrocytes as indicated by enlarged cell bodies within GFAP-positive cells and Iba1-positive activated microglia in α-syn PFF injected mouse brains. These results indicate that PFF-induced pathology could lead to astrocyte and/or microglia senescence in PD brains, which may contribute to neuropathology in this model. Targeting senescent cells using senolytics could therefore constitute a viable therapeutic option for the treatment of PD.
| S-EPMC8304385 | biostudies-literature
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.
| S-EPMC8558257 | biostudies-literature
Project description:BackgroundAlthough alpha-synuclein (SNCA) is crucial to the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), mutations in the gene appear to be rare. We have recently hypothesized that somatic mutations in early development could contribute to PD.MethodsExpanding on our recent negative small study, we used high-resolution melting (HRM) analysis to screen SNCA coding exons for somatic point mutations in DNA from 539 PD and DLB cerebellar samples, with two additional regions (frontal cortex, substantia nigra) for 20 PD cases. We used artificial mosaics to determine sensitivity where possible.ResultsWe did not detect any evidence of somatic coding mutations. Three cases were heterozygous for known silent polymorphisms. The protocol we used was sensitive enough to detect 5% to 10% mutant DNA.ConclusionUsing DNA predominantly from cerebellum, but also from frontal cortex and substantia nigra (n = 20 each), we have not detected any somatic coding SNCA point mutations.
| S-EPMC4190821 | biostudies-literature
Project description:Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) are known to increase the risk of developing Alzheimer disease and Parkinson's disease (PD). However, the potential role of TREM2 effect on synucleinopathy has not been characterized. In this study, we investigated whether loss of TREM2 function affects α-synucleinopathy both in vitro and in vivo. In vitro, BV2 microglial cells were exposed to α-synuclein (α-syn) in the presence or absence of TREM2 small interference RNA. For in vivo studies, wild-type controls and TREM2 gene knockout mice were intracranially injected in the substantia nigra with adeno-associated viral vectors expressing human α-syn (AAV-SYN) to induce PD. Our results revealed that knockdown of TREM2 aggravated α-syn-induced inflammatory responses in BV2 cells and caused greater apoptosis in SH-SY5Y cells treated with BV2-conditioned medium. In mice, TREM2 knockout exacerbated dopaminergic neuron loss in response to AAV-SYN. Moreover, both in vitro and in vivo TREM2 deficiency induced a shift from an anti-inflammatory toward a proinflammatory activation status of microglia. These data suggest that impairing microglial TREM2 signaling aggravates proinflammatory responses to α-syn and exacerbates α-syn-induced neurodegeneration by modulating microglial activation state.-Guo, Y., Wei, X., Yan, H., Qin, Y., Yan, S., Liu, J., Zhao, Y., Jiang, F., Lou, H. TREM2 deficiency aggravates α-synuclein-induced neurodegeneration and neuroinflammation in Parkinson's disease models.
| S-EPMC6902667 | biostudies-literature
Project description:Parkinson's disease (PD) is one of the most common neurodegenerative diseases. PD is pathologically characterized by the death of midbrain dopaminergic neurons and the accumulation of intracellular protein inclusions called Lewy bodies or Lewy neurites. The major component of Lewy bodies is α-synuclein (α-syn). Prion-like propagation of α-syn has emerged as a novel mechanism in the progression of PD. This mechanism has been investigated to reveal factors that initiate Lewy pathology with the aim of preventing further progression of PD. Here, we demonstrate that coxsackievirus B3 (CVB3) infection can induce α-syn-associated inclusion body formation in neurons which might act as a trigger for PD. The inclusion bodies contained clustered organelles, including damaged mitochondria with α-syn fibrils. α-Syn overexpression accelerated inclusion body formation and induced more concentric inclusion bodies. In CVB3-infected mice brains, α-syn aggregates were observed in the cell body of midbrain neurons. Additionally, α-syn overexpression favored CVB3 replication and related cytotoxicity. α-Syn transgenic mice had a low survival rate, enhanced CVB3 replication, and exhibited neuronal cell death, including that of dopaminergic neurons in the substantia nigra. These results may be attributed to distinct autophagy-related pathways engaged by CVB3 and α-syn. This study elucidated the mechanism of Lewy body formation and the pathogenesis of PD associated with CVB3 infection.
| S-EPMC8568191 | biostudies-literature
Project description:Abnormal accumulation and propagation of the neuronal protein α-synuclein has been hypothesized to underlie the pathogenesis of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Here we report a de novo-developed compound (NPT100-18A) that reduces α-synuclein toxicity through a novel mechanism that involves displacing α-synuclein from the membrane. This compound interacts with a domain in the C-terminus of α-synuclein. The E83R mutation reduces the compound interaction with the 80-90 amino acid region of α-synuclein and prevents the effects of NPT100-18A. In vitro studies showed that NPT100-18A reduced the formation of wild-type α-synuclein oligomers in membranes, reduced the neuronal accumulation of α-synuclein, and decreased markers of cell toxicity. In vivo studies were conducted in three different α-synuclein transgenic rodent models. Treatment with NPT100-18A ameliorated motor deficits in mThy1 wild-type α-synuclein transgenic mice in a dose-dependent manner at two independent institutions. Neuropathological examination showed that NPT100-18A decreased the accumulation of proteinase K-resistant α-synuclein aggregates in the CNS and was accompanied by the normalization of neuronal and inflammatory markers. These results were confirmed in a mutant line of α-synuclein transgenic mice that is prone to generate oligomers. In vivo imaging studies of α-synuclein-GFP transgenic mice using two-photon microscopy showed that NPT100-18A reduced the cortical synaptic accumulation of α-synuclein within 1 h post-administration. Taken together, these studies support the notion that altering the interaction of α-synuclein with the membrane might be a feasible therapeutic approach for developing new disease-modifying treatments of Parkinson's disease and other synucleinopathies.
| S-EPMC5840882 | biostudies-literature
Project description: Not available
| S-EPMC5628770 | biostudies-literature
Project description:Importance. Biological markers of Parkinson’s disease are essential for achieving disease modification. Objective. To determine the association of SNCA blood transcript levels with prevalence of Parkinson’s disease. Background. The SNCA locus is preferentially transcribed in neurons and blood cells. Non-coding genetic variants and neuronal aggregates of α-synuclein protein associate this locus with sporadic Parkinson’s disease and suggest a potential role for abnormal SNCA transcription in the disease mechanism. Here we investigated variation in intracellular SNCA gene expression and SNCA transcript isoform abundance in circulating blood cells of cases with PD and controls in a network of biobanks that represent regional, national, and international populations. Design, Setting, Participants. Three cross-sectional, case-control studies nested in observational biomarker studies. 222 cases with early-stage clinical PD and 183 controls were enrolled from 2005 to 2010 in the Harvard Biomarker Study (HBS) at two Harvard-affiliated tertiary care centers. 76 cases with dopamine transporter imaging (DAT)-confirmed PD and 42 controls were enrolled between August 2007 and December 2008 in the Blood α-Synuclein, Gene Expression and Smell Testing as Diagnostic and Prognostic Biomarkers in Parkinson’s Disease Study (PROBE) study from 22 US tertiary care centers. 202 DAT-confirmed cases with de novo PD and 138 controls were enrolled in the Parkinson’s Progression Markers Initiative (PPMI) between July 2010 and November 2012 from 22 US and international tertiary care centers. Main Outcome Measures. Association of intracellular SNCA transcript abundance with PD estimated on analog and digital expression platforms. Results. Reduced levels of SNCA transcripts were associated with early-stage clinical PD, neuroimaging-confirmed PD, and untreated, neuroimaging-confirmed PD in accessible, peripheral blood cells from a total of 863 individuals. SNCA expression was reduced by 17%, 22%, and 16% in cases compared to controls in the HBS, PROBE, and PPMI study with P values of 0.004, 0.025, and 0.018, respectively, after adjusting for clinical, hematological, and processing covariates. Specific SNCA transcripts with long 3’ untranslated regions (UTR) and those skipping exon 5 are implicated in the accumulation and mitochondrial targeting of α-synuclein protein in Parkinson’s pathology. These transcript isoforms were linked to PD through digital expression analysis. Individuals in the lowest quartile of SNCA expression values had covariate-adjusted odds ratios for PD of 2.14 (95% C. I. 1.1-4.1), 4.5 (95% C. I. 1.3-15), and 2.1 (1.1-4.0) compared to individuals in the highest quartile of expression values in the HBS, PROBE, and PPMI study, respectively. Conclusions and Relevance. Reduced levels of SNCA expression, particularly of disease-relevant transcripts with extended 3’ UTR or exon 5 skipping, are associated with early-stage PD. These findings support a potential role for SNCA as a transcriptional marker of PD and may have implications for patient stratification and risk assessment.
2015-06-01 | GSE57475 | GEO