Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

α-Synuclein blocks endoplasmic reticulum protein translocation in Parkinson’s disease [scRNA-seq]

ABSTRACT: The primary mechanism and subcellular localisation of α-synuclein toxicity in Parkinson’s disease pathogenesis remain unknown. We spatially and temporally resolved proteomic and transcriptomic changes in human iPSC-derived dopaminergic neurons with increasing burden of pathological α-synuclein. We found that misfolded α-synuclein proteoforms, signified by the formation of nanoscale intraneuronal puncta, are associated with impaired translocon function at the endoplasmic reticulum (ER). We show that α-synuclein interacts with Sec61A in iPSC-derived dopaminergic neurons and in post-mortem brain tissue from patients with Parkinson’s disease. This interaction interferes with the co-translational translocation of ER-processed proteins including the vacuolar-type ATPase V0a1 subunit, glucocerebrosidase, and Cathepsin B, causing defective organelle function such as reduced lysosomal acidification, leading to increased extracellular vesicle release of α-synuclein. Defective ER-translocation was associated with increased ribosomal UFMylation and proteasomal recruitment but not activation of the unfolded protein response. Reduction of pathological α-synuclein by either CRISPRi to decrease α-synuclein expression or pharmacological activation of proteasomal degradation with repurposed drugs mitigates the ER defect. Our study offers a unifying mechanistic link between α-synuclein pathology and dysregulation of diverse organelle-associated proteins that are both Sec61A translocon substrates and genetic modifiers of Parkinson’s disease risk. Our data also provide a therapeutic rationale for proteasomal activation in early Parkinson’s disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276559 | GEO | 2026/07/06

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

α-Synuclein blocks endoplasmic reticulum protein translocation in Parkinson’s disease [bulk RNA-seq]

Project description:The primary mechanism and subcellular localisation of α-synuclein toxicity in Parkinson’s disease pathogenesis remain unknown. We spatially and temporally resolved proteomic and transcriptomic changes in human iPSC-derived dopaminergic neurons with increasing burden of pathological α-synuclein. We found that misfolded α-synuclein proteoforms, signified by the formation of nanoscale intraneuronal puncta, are associated with impaired translocon function at the endoplasmic reticulum (ER). We show that α-synuclein interacts with Sec61A in iPSC-derived dopaminergic neurons and in post-mortem brain tissue from patients with Parkinson’s disease. This interaction interferes with the co-translational translocation of ER-processed proteins including the vacuolar-type ATPase V0a1 subunit, glucocerebrosidase, and Cathepsin B, causing defective organelle function such as reduced lysosomal acidification, leading to increased extracellular vesicle release of α-synuclein. Defective ER-translocation was associated with increased ribosomal UFMylation and proteasomal recruitment but not activation of the unfolded protein response. Reduction of pathological α-synuclein by either CRISPRi to decrease α-synuclein expression or pharmacological activation of proteasomal degradation with repurposed drugs mitigates the ER defect. Our study offers a unifying mechanistic link between α-synuclein pathology and dysregulation of diverse organelle-associated proteins that are both Sec61A translocon substrates and genetic modifiers of Parkinson’s disease risk. Our data also provide a therapeutic rationale for proteasomal activation in early Parkinson’s disease.

2026-07-06 | GSE276377 | GEO

Phenotypic manifestation of alpha-synuclein strains from Parkinson’s disease and multiple system atrophy in human dopaminergic neruons

Project description:Although α-synucleinis implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels of α-synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with a-synuclein triplication or controls where endogenous α-synuclein was imprinted into synthetic or disease-relevant conformations. We used α-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) .We found that a 2.5-fold increase in α-synuclein levels in α-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in α-synuclein gene expression.Transcriptomic analysis and isogenic correction of α-synuclein triplication revealed that intraneuronal α-synuclein levels solely and sufficiently explained vulnerability to cell death.

2020-09-02 | GSE149632 | GEO

Large-scale bidirectional arrayed CRISPR screens identify OXR1 and EMC4 as modifiers of α-synuclein aggregation

Project description:In synucleinopathies, including Parkinson’s disease, α-synuclein (α-Syn) misfolds and forms Ser129-phosphorylated aggregates (pSyn). Mitochondrial and lysosomal dysfunction, along with impairments in protein and organelle trafficking, exacerbate α-Syn pathology through poorly defined molecular mechanisms. We used CRISPR-mediated gene activation and ablation to systematically interrogate mitochondrial, trafficking and motility-related genes to identify pSyn regulators in HEK293 cells exposed to α-Syn fibrils. We found that activation of the mitochondrial protein OXR1 increased pSyn by impairing ATP synthesis and altering the mitochondrial membrane potential, whereas ablation of the endoplasmic reticulum (ER)-associated protein EMC4 reduced pSyn by enhancing ER-driven autophagic flux and lysosomal clearance. Assays with distinct strains of α-Syn fibrils revealed that OXR1 was preferentially synergistic with multiple system atrophy (MSA)-associated fibrils, whereas EMC4 broadly reduced pSyn across diverse α-Syn polymorphs. These findings were validated in human iPSC-derived cortical and dopaminergic neurons, with OXR1 preferentially driving somatic aggregation and EMC4 depleting both somatic and neuritic aggregates. This work identifies OXR1 and EMC4 as organelle-specific regulators of α-Syn proteostasis and underscores the involvement of mitochondrial and ER-lysosomal pathways in synucleinopathies.

2025-04-25 | GSE295558 | GEO

Expression data from fibroblasts, iPSCs and neurons with four copies of SNCA, and equivalent cell lines from an unaffected first degree relative

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 gene expression microarray study was carried out as part of the validation process for demonstrating that the generated iPSC lines are pluripotent. 15 samples were analysed: 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 eight neuronal samples (each iPSC line differentiated into a neuronal population enriched for dopaminergic neurons, at two different time points).

2011-09-14 | E-GEOD-28365 | biostudies-arrayexpress

Phenotypic manifestation of alpha-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons

Project description:Althougha-synuclein is implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels ofa-synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with a-synuclein triplication or controls where endogenous a-synuclein was imprinted into synthetic or disease-relevant conformations. We used a-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) or multiple system atrophy (n=5). We found that a 2.5-fold increase in a-synuclein levels in a-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in a-synuclein gene expression. Progressive neuronal loss was observed only in a-synuclein triplication neurons seeded with brain-amplified fibrils. Transcriptomic analysis and isogenic correction of a-synuclein triplication revealed that intraneuronalalpha-synuclein levels solely and sufficiently explained vulnerability to neuronal death

2021-04-13 | GSE171999 | GEO

Expression data from Parkison's iPSCs with four copies of SNCA, and equivalent cell lines from an unaffected first degree relative

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 gene expression microarray study was carried out as part of the validation process for demonstrating that the generated iPSC lines are pluripotent. 5 samples were analysed: two clonal iPSC lines from each of two genotypes (four in total; AST denoting alpha-synuclein triplication and NAS denoting normal alpha-synuclein), a human embryonic stem cell line (SHEF4). All cultured in self-renewal conditions, mTeSR1

2011-09-14 | E-GEOD-30792 | biostudies-arrayexpress

SNP data from genomic DNA from a subject, fibroblasts, iPSCs and neurons with four copies of SNCA, and genomic DNA from an unaffected first degree relative and equivalent cell lines

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

Interfering with aggregated α-synuclein in advanced melanoma leads to a major upregulation of MHC class II proteins

Project description:Melanoma is the most serious and deadly form of skin cancer and with progression to advanced melanoma, the intrinsically disordered protein α-synuclein is upregulated to high levels; and while toxic to dopaminergic neurons in Parkinson’s disease, it is highly beneficial for primary and metastatic melanoma cells. To gain detailed insights, both at the level of the proteome and the transcriptome, into this exact opposite role of α-synuclein in advanced melanoma, we performed proteomic studies of high-level α-synuclein-expressing primary and metastatic human melanoma cell lines and proteomic and transcriptomic studies of metastatic human melanoma xenografts treated systemically with the diphenyl-pyrazole small-molecule compound anle138b, which binds to and interferes with the oligomeric structure of α-synuclein. The results of these studies reveal that interfering with oligomerized α-synuclein in these tumor xenografts led to a substantial upregulation of expression of major histocompatibility complex proteins in the melanoma cells, the latter of which is pertinent to enhancing anti-melanoma immune responses.

2024-05-21 | GSE240854 | GEO

CHCHD2 Mutant Mice Link Mitochondrial Deficits to PD Pathophysiology

Project description:Mitochondrial dysfunction is a hallmark of Parkinson’s disease (PD), but the mechanisms by which it drives autosomal dominant and idiopathic forms of PD remain unclear. To investigate this, we generated and performed a comprehensive phenotypic analysis of a knock-in mouse model carrying the T61I mutation in the mitochondrial protein CHCHD2, which causes late-onset symptoms indistinguishable from idiopathic PD. We observed pronounced mitochondrial disruption in substantia nigra (SN) dopaminergic neurons, including distorted ultrastructure and CHCHD2 aggregation, as well as disrupted mitochondrial protein-protein interactions in brain lysates. These abnormalities were associated with a whole-body metabolic shift towards glycolysis, elevated mitochondrial ROS, and progressive accumulation of aggregated α-synuclein. In idiopathic PD, CHCHD2 gene expression also correlated with α-synuclein levels in vulnerable dopaminergic neurons, and CHCHD2 protein accumulated in early Lewy aggregates. These findings delineate a pathogenic cascade in which CHCHD2 accumulation impairs mitochondrial respiration and increases ROS production, driving α-synuclein aggregation and neurodegeneration.

2025-10-02 | GSE309202 | GEO

SNP data from genomic DNA from a subject, fibroblasts, iPSCs and neurons with four copies of SNCA, and genomic DNA from an unaffected first degree relative and equivalent cell lines

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data