Enriched environmental conditions modify the gut microbiome composition and fecal markers of inflammation in Parkinson’s disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE137213 | GEO | 2019/10/01
REPOSITORIES: GEO
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Project description:Enriched environmental conditions modify the gut microbiome composition and fecal markers of inflammation in Parkinson’s disease
| PRJNA564818 | ENA
Project description:Recent findings suggest an implication of the gut microbiome in Parkinson's disease (PD) patients. PD onset and progression has also been linked with various environmental factors such as physical activity, exposure to pesticides, head injury, nicotine, and dietary factors. In this study, we used a mouse model, overexpressing the complete human SNCA gene (SNCA-TG mice) modeling familial and sporadic forms of PD to study whether environmental conditions such as standard vs. enriched environment changes the gut microbiome and influences disease progression. We performed 16S rRNA DNA sequencing on fecal samples for microbiome analysis and studied fecal inflammatory calprotectin from the colon of control and SNCA-TG mice kept under standard environment (SE) and enriched environment (EE) conditions. The overall composition of the gut microbiota was not changed in SNCA-TG mice compared with WT in EE with respect to SE. However, individual gut bacteria at genus level such as Lactobacillus sp. was a significant changed in the SNCA-TG mice. EE significantly reduced colon fecal inflammatory calprotectin protein in WT and SNCA-TG EE compared to SE. Moreover, EE reduces the pro-inflammatory cytokines in the feces and inflammation inducing genes in the colon. Our data suggest that an enriched social environment has a positive effect on the induction of SNCA mediated inflammation in the intestine and by modulating anti-inflammatory gut bacteria.
| S-EPMC6842954 | biostudies-literature
Project description:SNCA protein product, a-synuclein, is widely renowned for its role in synaptogenesis and implication in both aging and Parkinson’s Disease (PD), but research efforts are still needed to elucidate its physiological functions and mechanisms of regulation. In this work, we aim to characterize SNCA-AS1, antisense transcript to the SNCA gene, and its implications in cellular processes. The overexpression of SNCA-AS1 upregulates both SNCA and a-synuclein, and through RNA-seq analysis we investigated the transcriptomic changes of which both genes are responsible. We highlight how they impact neurites extension and synapses’ biology, through specific molecular signatures. We report a reduced expression of markers associated with synaptic plasticity, and we specifically focus on GABAergic and dopaminergic synapses, for their relevance in aging processes and PD, respectively. A reduction in SNCA-AS1 expression leads to the opposite effect. As part of this signature is co-regulated by the two genes, we discriminate between functions elicited by genes specifically altered by SNCA-AS1 or SNCA’s overexpression, observing a relevant role for SNCA-AS1 in synaptogenesis through a shared molecular signature with SNCA. We also highlight how numerous deregulated pathways are implicated in aging-related processes, suggesting that SNCA-AS1 could be a key player in cellular senescence, with implications for aging-related diseases. Indeed, the upregulation of SNCA-AS1 leads to alterations in numerous PD specific genes, with an impact highly comparable to that of SNCA’s upregulation. Our results show that SNCA-AS1 elicits its cellular functions through the regulation of SNCA, with a specific modulation of synaptogenesis and senescence, presenting implications in PD.
2021-12-23 | GSE186255 | GEO
Project description:The glycine-51 (G51) codon in exon 3 of the rat Snca gene, encoding alpha-synuclein, was mutated to aspartic acid using CRISPR/Cas9 to generate the SncaG51D rat model of Parkinson’s (Morley et al. 2023). The G51D mutation causes an aggressive form of Parkinson’s and dementia with Lewy bodies in humans. The brains from four 6-month old rats of wild-type, heterozygous, and homozygous genotypes (Snca+/+, SncaG51D/+ and SncaG51D/G51D) were harvested and all 12 brains were bisected down the midline. Frontal cortex was isolated from one half, and synaptosomes were prepared from the other half. Following quality control the samples were processed for TMT-mass spectrometry by the Fingerprints Facility, University of Dundee. MaxQuant Version 1.6.0.16 was used for the assignment of peptides to protein using the uniport-rat-jan2018.fasta file. Pairwise comparisons were made between the different mutant samples and Snca+/+ for both the cortical and synaptosome samples. Morley V, Dolt KS, Alcaide-Corral CJ, Walton T, Lucatelli C, Mashimo T, Tavares AAS & Kunath T (2023) In vivo18F-DOPA PET imaging identifies a dopaminergic deficit in a rat model with a G51D α-synuclein mutation. Front. Neurosci. 17, 1095761.
2024-09-04 | PXD044776 | Pride
Project description:A major barrier to research on Parkinson’s disease (PD) is inaccessibility of diseased tissue for study. One solution is to derive induced pluripotent stem cells (iPSCs) from patients with PD and differentiate them into neurons affected by disease. We created an iPSC model of PD caused by triplication of SNCA encoding ?-synuclein. ?-Synuclein dysfunction is common to all forms of PD, and SNCA triplication leads to fully penetrant familial PD with accelerated pathogenesis. After differentiation of iPSCs into neurons enriched for midbrain dopaminergic subtypes, those from the patient contain double ?-synuclein protein compared to those from an unaffected relative, precisely recapitulating the cause of PD in these individuals. A measurable biomarker makes this model ideal for drug screening for compounds that reduce levels of ?-synuclein, and for mechanistic experiments to study PD pathogenesis. This SNP microarray study was carried out to confirm presence of SNCA triplication in the affected subject and the derived cell lines. 11 samples were analysed: genomic DNA from the two subjects in the study, the two parent fibroblast lines (AST denoting alpha-synuclein triplication and NAS denoting normal alpha-synuclein), two iPSC lines from each parent fibroblast line (four in total), a human embryonic stem cell line (SHEF4) and two neuronal samples one each from AST and NAS iPSCs).
2011-09-14 | E-GEOD-28366 | biostudies-arrayexpress
Project description:The Gut Microbiome in Parkinson’s Disease
| PRJNA671239 | ENA
Project description:The Gut Microbiome in Parkinson’s Disease
| PRJNA671238 | ENA
Project description:A major barrier to research on Parkinson’s disease (PD) is inaccessibility of diseased tissue for study. One solution is to derive induced pluripotent stem cells (iPSCs) from patients with PD and differentiate them into neurons affected by disease. We created an iPSC model of PD caused by triplication of SNCA encoding α-synuclein. α-Synuclein dysfunction is common to all forms of PD, and SNCA triplication leads to fully penetrant familial PD with accelerated pathogenesis. After differentiation of iPSCs into neurons enriched for midbrain dopaminergic subtypes, those from the patient contain double α-synuclein protein compared to those from an unaffected relative, precisely recapitulating the cause of PD in these individuals. A measurable biomarker makes this model ideal for drug screening for compounds that reduce levels of α-synuclein, and for mechanistic experiments to study PD pathogenesis. This SNP microarray study was carried out to confirm presence of SNCA triplication in the affected subject and the derived cell lines.
2011-09-15 | GSE28366 | GEO
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:Mutations in the SNCA gene cause autosomal dominant Parkinson’s disease (PD), with progressive loss of dopaminergic neurons in the substantia nigra, and accumulation of aggregates of α-synuclein. However, the sequence of molecular events that proceed from the SNCA mutation during development, to its end stage pathology is unknown. Utilising human induced pluripotent stem cells (hiPSCs) with SNCA mutations, we resolved the temporal sequence of pathophysiological events that occur during neuronal differentiation in order to discover the early, and likely causative, events in synucleinopathies. We adapted a small molecule-based protocol that generates highly enriched midbrain dopaminergic (mDA) neurons (>80%). We characterised their molecular identity using single-cell RNA sequencing and their functional identity through the synthesis and secretion of dopamine, the ability to generate action potentials, and form functional synapses and networks. RNA velocity analyses confirmed the developmental transcriptomic trajectory of midbrain neural precursors into different mDA neuronal clusters. To characterise the synucleinopathy, we adopted super-resolution methods to determine the number, size, and structure of aggregates in SNCA-mutant mDA neurons. By day 27 of differentiation, prior to maturation to mDA neurons of molecular and functional identity, we demonstrate the formation of small aggregates; specifically, β-sheet rich oligomeric aggregates, in SNCA-mutant midbrain immature neurons. The aggregation progresses over time to accumulate phosphorylated and fibrillar aggregates. When the midbrain neurons were functional, we observed impaired intracellular calcium signalling, evidenced with an increased basal calcium level and impairments in both cytosolic and mitochondrial calcium rearrangements. Once midbrain identity fully developed, SNCA-mutant neurons exhibited mitochondrial dysfunction, oxidative stress, lysosomal swelling as well as an upregulation of mitophagy and autophagy. In addition, SNCA-mutant neurons displayed pathophysiological excitability, revealed as a depolarised resting membrane potential, an increased input resistance, and impaired firing properties. Ultimately these multiple cellular stresses lead to an increase in cell death by day 62 post-differentiation. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD, and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.
2023-03-11 | PXD035500 | Pride