Dysregulated synaptic gene expression and axonal neuropathology in a human iPSC-based model of familial Parkinson's disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE84684 | GEO | 2017/04/23
SECONDARY ACCESSION(S): PRJNA330836
REPOSITORIES: GEO
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Project description: Not available
| S-EPMC5422768 | biostudies-literature
Project description:Disease-modifying therapies remain an important unmet need for neurodegenerative diseases, including Parkinson’s disease (PD). The aim of this study was to investigate the molecular pathways affected by the multi-kinase inhibitor BX795, which is neuroprotective in an induced pluripotent stem cell (iPSC)-based model of familial PD. To this end, we performed proteomics analysis in iPSC-derived neurons from patients bearing the G209A (p.A53T) α-synuclein (αSyn) mutation vis-à-vis control neurons, in the absence or presence of BX795. Comparison between p.A53T versus control neurons in the absence of BX795, revealed differential expression of 640 proteins from which only 67 were down-regulated whilst the rest 573 were up-regulated. This large increase in protein expression was linked by GO enrichment analysis mainly to the biological processes of transcription, translation, protein synthesis and modification. Upon treatment with BX795, the levels of a cohort of 118 proteins, lying mostly within these biological processes and representing approximately 20% of the total dysregulated proteins in p.A53T neurons, were restored. Enrichment analysis using the DAVID and Reactome softwares showed that these proteins are predominantly associated with mRNA metabolism, mRNA transport and translation, protein metabolism and degradation processes. This outcome was specific to p.A53T-neurons as BX795 had no significant effect on the proteome of control neurons.
2023-03-10 | PXD019574 | Pride
Project description:The fact that Parkinsons disease (PD) can arise from numerous genetic mutations suggests a unifying molecular pathology underlying the various genetic backgrounds. In order to address this hypothesis, an integrated approach utilizing in vitro disease modeling and comprehensive transcriptome profiling was taken to advance our understanding of PD progression and the concordant downstream signaling pathways across divergent genetic predispositions. To model PD in vitro, neurons harboring disease-causing mutations were generated from patient-specific, induced pluripotent stem cells (iPSCs) and found to recapitulate several disease-related phenotypes. Signs of degeneration in PD midbrain dopaminergic (mDA) neurons were observed, reflecting the cardinal feature of PD. In addition, novel gene expression signatures were revealed for PD mDA neurons, providing molecular insights to disease phenotype observed in vitro, including oxidative stress vulnerability and altered neuronal activity. Notably, detailed transcriptome profiling of PD neurons showed that elevated RBFOX1, a gene previously linked to neurodevelopmental diseases, is responsible for a pattern of alternative RNA processing associated with PD-specific phenotypes in vitro.
2016-06-07 | E-MTAB-4586 | biostudies-arrayexpress
Project description:Parkinson's disease (PD) is a progressive neurodegenerative disorder, which is characterised by degeneration of distinct neuronal populations, including dopaminergic neurons of the substantia nigra. Here, we use a metabolomics profiling approach to identify changes to lipids in PD observed in sebum, a non-invasively available biofluid. We used liquid chromatography-mass spectrometry (LC-MS) to analyse 274 samples from participants (80 drug naïve PD, 138 medicated PD and 56 well matched control subjects) and detected metabolites that could predict PD phenotype. Pathway enrichment analysis shows alterations in lipid metabolism related to the carnitine shuttle, sphingolipid metabolism, arachidonic acid metabolism and fatty acid biosynthesis. This study shows sebum can be used to identify potential biomarkers for PD.
2020-12-21 | MTBLS2266 | MetaboLights
Project description:The overall goal was to identify changes in gene expression following treatment with aSYN F110 compared to control (untreated). Alpha-synuclein (αSYN) protein has been observed in reactive astrocytes in PD patients’ brains, raising the question of how αSYN, neuroinflammation, and astrocytes interact in PD pathogenesis. Here, we examined the cellular changes triggered by tumor necrosis factor alpha (TNFα) and different αSYN species in astrocytes derived from induced pluripotent stem cells. Human astrocytes treated with TNFα displayed a strong reactive pro-inflammatory phenotype with upregulation of pro-inflammatory gene networks, activation of the NF-kB pathway, and release of pro-inflammatory cytokines, whereas those treated with high molecular weight αSYN fibrils acquired a reactive antigen (cross-)presenting phenotype with upregulation of MHC genes and increased HLA-DR/DQ/DP and HLA-F molecules at the cell surface. Surprisingly, cell surface location of MHC proteins was abrogated by larger F110 fibrils polymorph, despite the upregulation of MHC genes. A proteomics investigation further confirmed a direct interaction between astrocytic MHC proteins and αSYN fibril peptides. Interestingly, TNFα and αSYN fibrils competed to drive the astrocyte immune reactive response. The astrocyte immune responses were accompanied by an impaired ATP-generating mitochondrial respiration, which was exacerbated in PD astrocytes containing a PARK2-variant. Our data provide evidence for astrocytic involvement in PD pathogenesis and reveal their complex immune reactive responses to exogenous stressors.
2021-02-16 | GSE166769 | GEO
Project description:The overall goal was to identify changes in gene expression following treatment with TNFa, monomeric, or fibril aSYN compared to control (untreated). Alpha-synuclein (αSYN) protein has been observed in reactive astrocytes in PD patients’ brains, raising the question of how αSYN, neuroinflammation, and astrocytes interact in PD pathogenesis. Here, we examined the cellular changes triggered by tumor necrosis factor alpha (TNFα) and different αSYN species in astrocytes derived from induced pluripotent stem cells. Human astrocytes treated with TNFα displayed a strong reactive pro-inflammatory phenotype with upregulation of pro-inflammatory gene networks, activation of the NF-kB pathway, and release of pro-inflammatory cytokines, whereas those treated with high molecular weight αSYN fibrils acquired a reactive antigen (cross-)presenting phenotype with upregulation of MHC genes and increased HLA-DR/DQ/DP and HLA-F molecules at the cell surface. Surprisingly, cell surface location of MHC proteins was abrogated by larger F110 fibrils polymorph, despite the upregulation of MHC genes. A proteomics investigation further confirmed a direct interaction between astrocytic MHC proteins and αSYN fibril peptides. Interestingly, TNFα and αSYN fibrils competed to drive the astrocyte immune reactive response. The astrocyte immune responses were accompanied by an impaired ATP-generating mitochondrial respiration, which was exacerbated in PD astrocytes containing a PARK2-variant. Our data provide evidence for astrocytic involvement in PD pathogenesis and reveal their complex immune reactive responses to exogenous stressors.
2021-02-16 | GSE166768 | GEO
Project description:Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that is characterized by the selective loss of midbrain dopamine (DA)-producing neurons and the formation of α-synuclein (α-syn)-containing inclusions named Lewy bodies (LBs). Here, we report that the loss of glucocerebrosidase (GCase), coupled with α-syn overexpression, result in substantial accumulation of detergent-resistant α-syn aggregates and Lewy body-like inclusions (LBLIs) in human midbrain-like organoids (hMLOs). These LBLIs exhibit a highly similar structure to PD-associated LBs, by displaying a spherically symmetric morphology with an eosinophilic core, and containing α-syn and ubiquitin. Importantly, hMLOs generated from PD patient-derived inducible pluripotent stem cells (iPSCs) harboring SNCA triplication also exhibit subsequent degeneration of DA neurons and LBLI formation upon chronic GCase inhibitor treatment. Taken together, our hMLOs harbouring two major PD risk factors (GCase deficiency and overproduced α-syn) successfully recapitulate major pathophysiological signatures of the disease, and highlight the broad utility of brain organoid technology in modeling human neurodegenerative diseases.
2021-08-13 | E-MTAB-7302 | biostudies-arrayexpress
Project description:Parkinson’s Disease (PD) is a common neurodegenerative disorder affecting millions of people worldwide for which there are only symptomatic therapies. Small molecules able to target key pathological processes in PD have emerged as interesting options for modifying disease progression. We have previously shown that a (poly)phenol-enriched fraction (PEF) of Corema album L. leaf extract modulates central events in PD pathogenesis, namely α-synuclein (αSyn) toxicity, aggregation and clearance. PEF was now subjected to a bio-guided fractionation with the aim of identifying the critical bioactive compound. We identified genipin, an iridoid, which relieves αSyn toxicity and aggregation. Furthermore, genipin promotes metabolic alterations and modulates lipid storage and endocytosis. Importantly, genipin was able to prevent the motor deficits caused by the expression of αSyn-GFP in a Drosophila melanogaster model of PD. These findings open new avenues for the exploitation of genipin for PD therapeutics.
2023-04-06 | GSE226744 | GEO
Project description:Synucleinopathies are triggered by the aggregation of α-synuclein (αSyn), leading to progressive neurodegeneration. However, the intracellular mechanism of αSyn aggregation remains unclear. Here we show that assembly of RNA G-quadruplexes (rG4s) form scaffolds for αSyn aggregation, contributing to neurodegeneration. Purified αSyn binds rG4s directly through the N-terminus. rG4 itself undergoes phase separation and assembly by Ca2+, accelerating the sol-gel phase transition of αSyn. In αSyn preformed fibrils (PFF)-treated neurons, rG4s assembly composed of synaptic mRNAs co-aggregates with αSyn upon Ca2+ excess influx into cytoplasm, eliciting synaptic dysfunction. Artificial assembly of rG4s using an optogenetic approach evokes αSyn aggregation and neuronal dysfunction. Administration of 5-aminolevulinic acid (5-ALA), a prodrug of protoporphyrin IX (PpIX) that prevents phase separation of rG4s, attenuating αSyn aggregation, neurodegeneration, and progressive motor deficits in PFF-injected synucleinopathy mice. Together, assembly of rG4s due to dysregulation of intracellular Ca2+ homeostasis accelerates αSyn phase transition and aggregation may contribute to pathogenesis of synucleinopathies.
2023-07-18 | GSE234238 | GEO
Project description:Parkinson's disease (PD) is defined by the degeneration of nigral dopaminergic (DA) neurons and can be caused by monogenic mutations of genes such as parkin. The lack of phenotype in parkin knockout mice suggests that human nigral DA neurons have unique vulnerabilities. Here we generate induced pluripotent stem cells from normal subjects and PD patients with parkin mutations. We demonstrate that loss of parkin in human midbrain DA neurons greatly increases the transcription of monoamine oxidases and oxidative stress, significantly reduces DA uptake and increases spontaneous DA release. Lentiviral expression of parkin, but not its PD-linked mutant, rescues these phenotypes. The results suggest that parkin controls dopamine utilization in human midbrain DA neurons by enhancing the precision of DA neurotransmission and suppressing dopamine oxidation. Thus, the study provides novel targets and a physiologically relevant screening platform for disease-modifying therapies of PD. Genomic DNA was isolated from each of the four lines of iPSCs and labeled with Cy5. Pooled sex mismatched normal human genomic DNA was labeled with Cy3. Both samples are hybridized together on RPCI 21K BAC aCGH array.
2012-01-21 | E-GEOD-35190 | biostudies-arrayexpress