Project_Summary_Rat_primary_cortical_neurons_asyn_3K_RNA_Seq
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE172385 | GEO | 2021/07/19
REPOSITORIES: GEO
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Project description:BACKGROUND: Synucleinopathy disorders are characterized by aggregates of α-synuclein (α-syn), which engage microglia to elicit a neuroinflammatory response. However, the influence α-syn has on DNA methylation and gene expression patterns for other genes has not been thoroughly explored. Our objective is to determine gene expression and methylation changes in microglia induced by aggregate α-syn.METHODS: Transgenic mThy1-Asyn mice overexpressing human α-syn are a model of synucleinopathy. Microglia from 3 and 13-month-old mice were used to isolate nucleic acids for methylated DNA and RNA-sequencing. α-Syn-induced changes in gene expression and genomic methylation were determined and examined for functional enrichment followed by network analysis to further elucidate possible connections within the data.RESULTS: Microglial DNA isolated from our 3-month cohort had 5,315 differentially methylated gene (DMG) changes, while RNA levels demonstrated a change in 119 differentially expressed genes (DEGs) between mThy1-Asyn mice and wild-type littermate controls. The 3-month DEGs and DMGs were highly associated with adhesion and migration signaling, suggesting a phenotypic transition from resting to active microglia. We observed 3,742 DMGs and 3,766 DEGs in 13-month mThy1-Asyn mice.These genes were often related to adhesion, migration, cell cycle, cellular metabolism, and immune response. Network analysis also showed increased cell mobility and inflammatory functions at 3 months, shifting to cell cycle, immune response, and metabolism changes at 13 months.CONCLUSION: We observed significant α-syn-induced methylation and gene expression changes in microglia. Our data suggest that α-syn overexpression initiates microglial activation leading to neuroinflammation and cellular metabolic stresses, which is associated with disease progression.
2021-07-02 | GSE158981 | GEO
Project description:BACKGROUND: Synucleinopathy disorders are characterized by aggregates of α-synuclein (α-syn), which engage microglia to elicit a neuroinflammatory response. However, the influence α-syn has on DNA methylation and gene expression patterns for other genes has not been thoroughly explored. Our objective is to determine gene expression and methylation changes in microglia induced by aggregate α-syn.METHODS: Transgenic mThy1-Asyn mice overexpressing human α-syn are a model of synucleinopathy. Microglia from 3 and 13-month-old mice were used to isolate nucleic acids for methylated DNA and RNA-sequencing. α-Syn-induced changes in gene expression and genomic methylation were determined and examined for functional enrichment followed by network analysis to further elucidate possible connections within the data.RESULTS: Microglial DNA isolated from our 3-month cohort had 5,315 differentially methylated gene (DMG) changes, while RNA levels demonstrated a change in 119 differentially expressed genes (DEGs) between mThy1-Asyn mice and wild-type littermate controls. The 3-month DEGs and DMGs were highly associated with adhesion and migration signaling, suggesting a phenotypic transition from resting to active microglia. We observed 3,742 DMGs and 3,766 DEGs in 13-month mThy1-Asyn mice.These genes were often related to adhesion, migration, cell cycle, cellular metabolism, and immune response. Network analysis also showed increased cell mobility and inflammatory functions at 3 months, shifting to cell cycle, immune response, and metabolism changes at 13 months.CONCLUSION: We observed significant α-syn-induced methylation and gene expression changes in microglia. Our data suggest that α-syn overexpression initiates microglial activation leading to neuroinflammation and cellular metabolic stresses, which is associated with disease progression.
2021-07-02 | GSE158980 | GEO
Project description:The accumulation of α-synuclein (ASyn) has been observed in several lysosomal storage diseases (LSD), but it remains unclear if the accumulation of ASyn contributes to the pathology. The mitochondria degeneration, reduced expression of manganese superoxide dismutase 2, and reactive oxygen species-mediated oxidative damage were observed in the neurons of Hexb-/- mice. Gene expression in the brain of 14-week-old Hexb-/- ASyn+/+, Hexb-/- Asyn-Tg, and Hexb-/- ASyn-/- mice were analyzed.
2015-05-12 | E-GEOD-68748 | biostudies-arrayexpress
Project description:Parkinson’s disease (PD) is a neurodegenerative disorder associated with the accumulation of intraneuronal protein aggregates called Lewy bodies. These inclusions contain aberrantly folded and aggregated alpha-synuclein (aSyn), a key protein involved in the pathology of PD, for which the mechanisms of toxicity are still largely unknown. Recent studies suggest that the conformational changes occurring during aSyn aggregation process can be expected to lead to alterations in the interactome of aSyn. Therefore, identifying changes in the interactome of monomeric and aggregated states of aSyn could help to understand the underlying molecular mechanisms of PD. Despite substantial efforts, current interactomics approaches do not enable determining structure-specific PPIs and their interaction interfaces on a proteome-wide scale. To address this limitation, we here applied the structural proteomics method limited proteolysis–mass spectrometry to systematically identify structure-specific PPIs of aSyn by probing protein structural alterations within cellular extracts upon treatment with monomeric and aggregated, fibrillar states of aSyn. Overall, we identified several previously known interactors of both monomeric and aggregated aSyn as well as novel putative structure-specific interactors including their interaction interfaces and protein binding parameters in situ. These results may constitute an important step in the understanding of how distinct structural states of disease-associated proteins are involved in disease mechanisms.
2024-02-10 | PXD039784 | Pride
Project description:Parkinsonâs disease (PD) and Dementia with Lewy bodies (DLB) are the two most common examples of synucleinopathies, i.e. human disorders that display intracellular deposition of the Alpha-synuclein (aSYN) protein. The two forms of aSYN deposits, intracellular Lewy bodies and Lewy neurites, are in the PD brain primarily found in the substantia nigra whereas in DLB brains they are diffusely spread in cortical and limbic areas. We are currently analyzing the protective effects on aSYN pathology by the molecular chaperone hsp70 in mice overexpressing wildtype human aSYN. Moreover, transgenic mice overexpressing hsp70 have been cross-bred with the aSYN mouse line. Intriguingly, the aSYN / hsp70 double transgenics display a pronounced reduction in biochemically assessed aSYN aggregation. Gene expression of these mice will not only provide insight into the disease mechanisms of aSYN pathology but its prevention by the overexpression of hsp70, leading to new potential avenues of treatment. Project 1: To investigate and compare alterations in gene expression profiles of brains from wild-type mice and mice overexpressing wildtype human aSYN, human hsp70 and aSYN / hsp70, respectively. The comparison of the expression profiles of the groups of mice: aSYN, Hsp70, aSYN/ Hsp70 and non-transgenic littermates will help to identify the genes that are involved in the mediation of aggregation toxicity of aSYN expression as well as the genes that may mediate an attenuation of aSYN pathology in hsp70-coexpressors. Project 1: Selection of animals Mice of 4 month old (n=6) of age of each background (aSYN, Hsp70, aSYN/ Hsp70 and non-transgenic littermates) will be used for RNA-extraction for a total of 24 mice. Preparation of samples For the proposed experiments, we will use the recommended procedures, as outlined by the consortium, for extracting and purifying RNA from whole brain homogenate. Briefly, RNA will be extracted by the trizol method and purified by using the RNeasy MinElute Cleanup (QIAGEN Inc., USA). RNA labeling and hybridization procedures will be carried out by the microarray consortium. SPECIAL NOTE: The samples will be sent upon availability. Gene Expression Microarray Analysis Six mice will be included in each group per timepoint to generate statistically testable data and limit the possible confound of individual mouse gene expression variations. The genome expression will be evaluated through the use of the GeneChip® Mouse Genome 430 2.0 Array (Affymetrix) for each individual mouse constituting a total of 24 arrays for the proposed study. Gene expression data interpretation will be assisted by the Microarray Consortium Center bioinformatics core.
2008-06-13 | E-GEOD-4758 | biostudies-arrayexpress
Project description:To determine whether early-stage ovarian high grade serous carcinoma (HGSC) represents a distinct genomic entity, we collected samples from 43 patients with stage IA-IIA HGSC to identify potential differences in short genomic variants and copy number aberrations, and compared them to a cohort of 52 late-stage (stage IIIC-IV) cases. We found no significant differences in somatic mutations or focal copy number alterations between early-stage and late-stage cohorts. There was, however, a significant difference in both ploidy and copy number signature exposure between early and late-stage samples, with higher ploidy and signature 4 exposure in late-stage cases. Unsupervised hierarchical clustering revealed three clusters, which were prognostic. Together, our data suggest that early and late-stage HGSC share fundamental genomic features, but that late- stage disease appears distinct from early-stage, with evidence of whole genome duplication that may provide evolutionary benefit.
| EGAS00001005567 | EGA
Project description:Parkinson’s disease (PD) is characterized by multiple symptoms including olfactory dysfunction, whose underlying mechanisms remain unclear. Here, we explored pathologic changes in the olfactory pathway of transgenic (Tg) mice of both sexes expressing the human A30P mutant α-synuclein (α-syn; α-syn-Tg mice) at 6–7 and 12–14 months of age, representing early and late-stages of motor progression, respectively. α-Syn-Tg mice at late stages exhibited olfactory behavioral deficits, which correlated with severe α-syn pathology in projection neurons (PNs) of the olfactory pathway. In parallel, olfactory bulb (OB) neurogenesis in α-syn-Tg mice was reduced in the OB granule cells at six to seven months and OB periglomerular cells at 12–14 months, respectively, both of which could contribute to olfactory dysfunction. Proteomic analyses showed a disruption in endocytic and exocytic pathways in the OB during the early stages which appeared exacerbated at the synaptic terminals when the mice developed olfactory deficits at 12–14 months. Our data suggest that (1) the α-syn-Tg mice recapitulate the olfactory functional deficits seen in PD; (2) olfactory structures exhibit spatiotemporal disparities for vulnerability to α-syn pathology; (3) α-syn pathology is restricted to projection neurons in the olfactory pathway; (4) neurogenesis in adult α-syn-Tg mice is reduced in the OB; and (5) synaptic endocytosis and exocytosis defects in the OB may further explain olfactory deficits.
2023-01-13 | PXD039396 | Pride
Project description:α-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson’s disease (PD). It is primarily cytosolic and reversibly interacts with cell membranes. α-Syn also occurs in the nucleus, however, the mechanisms involved in its nuclear localization are poorly understood. We analyzed alterations in gene expression following induced α-Syn expression in SH-SY5Y cells. Analysis for upstream regulators pointed at alterations in transcription activity of retinoic acid receptors (RAR)s and additional nuclear receptors. We show that α-Syn binds RA and translocates to the nucleus to selectively enhance gene transcription. Nuclear translocation of α-Syn is regulated by calreticulin, in a leptomycin-B independent mechanism. Importantly, nuclear translocation of α-Syn following RA treatment enhances its toxicity in cultured neurons and the expression levels of PD-associated genes, among which are two familial PDassociated genes, ATPase cation transporting 13A2 (ATP13A2) and PTEN-induced kinase 1 (PINK1). The results link a physiological role for α-Syn in the regulation of RAmediated gene transcription and its toxicity in the synucleinopathies.
2020-02-24 | GSE145804 | GEO
Project description:In this study, we used a cardiac-specific, inducible expression system to activate YAP in adult mouse heart. Activation of YAP in adult heart promoted cardiomyocyte proliferation and did not deleteriously affect heart function. Furthermore, YAP activation after myocardial infarction (MI) preserved heart function and reduced infarct size. Using adeno-associated virus subtype 9 (AAV9) as a delivery vector, we expressed human YAP in the murine myocardium immediately after MI. We found that AAV9:hYAP significantly improved cardiac function and mouse survival. AAV9:hYAP did not exert its salutary effects by reducing cardiomyocyte apoptosis. Rather, we found that AAV9:hYAP stimulated adult cardiomyocyte proliferation. Gene expression profiling indicated that AAV9:hYAP stimulated cell cycle gene expression, enhanced TGFβ-signaling, and activated of components of the inflammatory response.Cardiac specific YAP activation after MI mitigated myocardial injury after MI, improved cardiac function and mouse survival. These findings suggest that therapeutic activation of hYAP or its downstream targets, potentially through AAV-mediated gene therapy, may be a strategy to improve outcome after MI. Three groups were involved in this study: sham group, AAV9:Luci+MI group and AAV9-YAP+MI group. Each group contained three biological replicates. The sham group had neither myocardial infarction nor AAV injection. The AAV9:Luci +MI(L for brief) group had myocardial infarction and injected with AAV9:Luic. The AAV9:hYAP+MI(YAP for brief) group had myocardial infarction and injected with AAV9:hYAP. 5 days after MI and AAV injection, the heart apexes were collected and the total RNA were isolated for microarray analysis.
2014-05-26 | E-GEOD-54612 | biostudies-arrayexpress
Project description:Purpose: The goals of this study are to identify cellular pathways to recover a-syn aggregation-mediated toxicity induced in response to CDC or BAG treatment on PD-iPSC derived mDA neurons. Methods: mRNA profiles of 30-day-old PD-mDA neurons with CDC or BAG treatment for 1 day were generated by deep sequencing, in duplicate, using Illumina HiSeq. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: Burrows–Wheeler Aligner (BWA) followed by ANOVA (ANOVA) and TopHat followed by Cufflinks. Conclusions: Our study represents the detailed analysis of mDA neuronal transcriptomes in response to CDC or BAG treatments, with biologic replicates, generated by RNA-seq technology. Our results show that CDC or BAG treatment could rescue the toxcity from a-syn aggregation via purine metabolism / ion transport pathways.
2021-06-30 | GSE153325 | GEO