Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson's patients
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ABSTRACT:
SUBMITTER: Dr. Laura de Boni
PROVIDER: S-SCDT-10_1038-S44321-024-00083-5 | biostudies-other |
REPOSITORIES: biostudies-other
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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:Currently, several ?-synuclein immunotherapies are being tested in experimental Parkinson's disease models and in clinical trials. Recent research has revealed that ?-synuclein is not just an intracellular synaptic protein but also exists extracellularly. Moreover, the transfer of misfolded ?-synuclein between cells might be a crucial step in the process leading to a progressive increase in deposition of ?-synuclein aggregates throughout the Parkinson's disease brain. The revelation that ?-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 ?-synucleinopathies and highlight the likely important role of microglia in clearing misfolded ?-synuclein from the extracellular space.
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Project description:Silica nanoparticles (SiO2 NPs) are increasingly investigated for their potential in drug delivery systems. However, the neurotoxicity of SiO2 NPs remains to be fully clarified. Previously SiO2 NPs have been reported to be detected in the central nervous system, especially in the dopaminergic neurons which are deeply involved in Parkinson's disease (PD). In this article, we characterized the effects of SiO2 NPs on inducing PD-like pathology both in vitro and in vivo. Results showed that SiO2 NPs promote more severe hyperphosphorylation and aggregation of α-synuclein, mitochondria impairment, oxidative stress, autophagy dysfunction, and neuronal apoptosis in the α-Syn A53T transgenic mice intranasally administrated with SiO2 NPs compared with the control group. Our findings provide new evidence supporting that SiO2 NPs exposure might have a strong capability of promoting the initiation and development of PD.
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Project description:Recent studies have identified increasing levels of nanoplastic pollution in the environment. Here we find that anionic nanoplastic contaminants potently precipitate the formation and propagation of α-synuclein protein fibrils through a high-affinity interaction with the amphipathic and non-amyloid component (NAC) domains in α-synuclein. Nanoplastics can internalize in neurons through clathrin-dependent endocytosis, causing a mild lysosomal impairment that slows the degradation of aggregated α-synuclein. In mice, nanoplastics combine with α-synuclein fibrils to exacerbate the spread of α-synuclein pathology across interconnected vulnerable brain regions, including the strong induction of α-synuclein inclusions in dopaminergic neurons in the substantia nigra. These results highlight a potential link for further exploration between nanoplastic pollution and α-synuclein aggregation associated with Parkinson's disease and related dementias.
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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
Project description:The present study was to evaluate the diagnostic value of salivary total and oligomeric α-synuclein levels in PD. Furthermore, we sought to explore the relationship between salivary total α-synuclein and α-synuclein SNP variants levels. 201 PD patients and 67 controls were recruited, of which there also had the genetic information of two positive α-synuclein (SNCA) loci. Salivary total α-synuclein was assayed using a highly sensitive Luminex assay and oligomeric α-synuclein was quantified by the combination of Gel filtration chromatography and Western blot, respectively. From our analysis,No difference in salivary total α-synuclein levels was found between PD patients and healthy controls, it decreased with age in PD patients, and was closely associated with genotypic distribution of rs11931074 and rs894278 in PD, respectively. After controlled for age and genders, G allele of rs11931074 was correlated with lower salivary total α-synuclein levels, while G allele of rs894278 was also correlated with the higher levels. Simultaneously, the further study was shown that salivary oligomeric α-synuclein in PD patients significantly increased comparing to healthy controls. In conclusions,our study firstly demonstrated that salivary total α-synuclein levels could be manipulated by different α-synuclein SNPs and salivary oligomeric α-synuclein could be a potential diagnostic indicator of PD.
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Project description:Parkinson's disease is a neurodegenerative disease characterized by the formation of neuronal inclusions of α-synuclein in patient brains. As the disease progresses, toxic α-synuclein aggregates transmit throughout the nervous system. No effective disease-modifying therapy has been established, and preventing α-synuclein aggregation is thought to be one of the most promising approaches to ameliorate the disease. In this study, we performed a two-step screening using the thioflavin T assay and a cell-based assay to identify α-synuclein aggregation inhibitors. The first screening, thioflavin T assay, allowed the identification of 30 molecules, among a total of 1262 FDA-approved small compounds, which showed inhibitory effects on α-synuclein fibrilization. In the second screening, a cell-based aggregation assay, seven out of these 30 candidates were found to prevent α-synuclein aggregation without causing substantial toxicity. Of the seven final candidates, tannic acid was the most promising compound. The robustness of our screening method was validated by a primary neuronal cell model and a Caenorhabditis elegans model, which demonstrated the effect of tannic acid against α-synuclein aggregation. In conclusion, our two-step screening system is a powerful method for the identification of α-synuclein aggregation inhibitors, and tannic acid is a promising candidate as a disease-modifying drug for Parkinson's disease.
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Project description:Parkinson's disease can manifest either as a sporadic form, which is common, or as an inherited autosomal dominant trait resulting from missense mutations. Recently, the novel α-synuclein variant V15A was identified in two Caucasian and two Japanese families with Parkinson's disease. Using a combination of NMR spectroscopy, membrane binding assays and aggregation assays we show that the V15A mutation does not strongly perturb the conformational ensemble of monomeric α-synuclein in solution, but weakens its affinity for membranes. Attenuated membrane binding raises the concentration of the aggregation-prone disordered α-synuclein in solution, allowing only the V15A variant but not wild-type α-synuclein to form amyloid fibrils in the presence of liposomes. These findings, together with earlier research on other missense mutations of α-synuclein, suggest that maintaining a balance between membrane-bound and free aggregation-competent α-synuclein is critical in α-synucleinopathies.
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Project description:ObjectiveTo determine whether blood cells expressed α-Syn can differentiate Parkinson's disease (PD) from healthy controls (HC).MethodsThe concentrations of α-Syn were determined in samples of blood cell pellets using a quantitative Lipid-ELISA assay. In addition, the levels of total protein, hemoglobin, iron and H-ferritin were determined. The study includes samples from the Biofind cohort (n = 46 PD and 45 HC) and results were validated with an additional cohort (n = 35 PD and 28 HC).ResultsA composite biomarker consisting of the concentrations of total α-Syn, proteinase-K resistant (PKres ) α-Syn and phospho-Serine 129 α-Syn (PSer 129), is designed based on the analysis of the discovery BioFIND cohort. This composite biomarker differentiates a PD subgroup, presenting motor symptoms without dementia from a HC group, with a convincing accuracy, represented by an AUC = 0.81 (95% CI, 0.71 to 0.92). Closely similar results were obtained for the validation cohort, that is, AUC = 0.81, (95% CI, 0.70 to 0.94).InterpretationOur results demonstrate the potential usefulness of blood cells expressed α-Syn as a biomarker for PD.
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Project description:Abnormal accumulation of α-synuclein contributes to the formation of Lewy bodies in the substantia nigra, which is considered the typical pathological hallmark of Parkinson's disease. Recent research indicates that angiotensin-(1-7) plays a crucial role in several neurodegenerative disorders, including Parkinson's disease, but the underlying mechanisms remain elusive. In this study, we used intraperitoneal administration of rotenone to male Sprague-Dawley rats for 4 weeks to establish a Parkinson's disease model. We investigated whether angiotensin-(1-7) is neuroprotective in this model by continuous administration of angiotensin-(1-7) into the right substantia nigra for 4 weeks. We found that angiotensin-(1-7) infusion relieved characteristic parkinsonian behaviors and reduced α-synuclein aggregation in the substantia nigra. Primary dopaminergic neurons were extracted from newborn Sprague-Dawley rat substantia nigras and treated with rotenone, angiotensin-(1-7), and/or the Mas receptor blocker A-779 for 24 hours. After binding to the Mas receptor, angiotensin-(1-7) attenuated apoptosis and α-synuclein aggregation in rotenone-treated cells. Primary dopaminergic neurons were also treated with angiotensin-(1-7) and/or the autophagy inhibitor 3-methyladenine for 24 hours. Angiotensin-(1-7) increased α-synuclein removal and increased the autophagy of rotenone-treated cells. We conclude that angiotensin-(1-7) reduces α-synuclein aggregation by alleviating autophagy dysfunction in Parkinson's disease. Therefore, the angiotensin-(1-7)/Mas receptor axis plays an important role in the pathogenesis of Parkinson's disease and angiotensin-(1-7) has potential therapeutic value for Parkinson's disease. All experiments were approved by the Biological Research Ethics Committee of Nanjing First Hospital (approval No. DWSY-2000932) in January 2020.
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