Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cholesterol enhances lysosome-autophagosome fusion for better α-synuclein clearance in GBA L444P mutated Parkinson’s disease

ABSTRACT: Mutations in the glucocerebrosidase (GBA) gene, the most common genetic risk factor for Parkinson’s disease (PD), exacerbate α-synuclein pathology through unclear mechanisms. We found that GBA-mutated PD patients show reduced serum cholesterol. Introducing the most common GBA variant in our cohort, L444P, into mice with human α-synuclein knock-in background exhibits behavioral and molecular pathological PD features by 12 months. Lysosomal proteomics identifies loss of lysosome-cytoplasmic vesicle interactions and loss of cholesterol-containing lipid microdomains in patients and mice. Autophagic flux monitoring reveals impaired autophagosome-lysosome fusion in Gba L444P mouse neurons. Gain- and loss-of-function experiments uncover cholesterol synthesis impairment via glycosphingolipid-reduced SREBP2 levels in neurons. Cholesterol supplementation enhances autophagic flux and mitigates α-synuclein accumulation in vitro, whereas AAV-Srebp2 delivery increases α-synuclein clearance in Gba L444P mice. Our study provides novel animal models and mechanistic insights into the GBA-associated PD and offers a new therapeutic paradigm by facilitating cholesterol-associated α-synuclein autophagic clearance.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yunlong Yang

PROVIDER: PXD077686 | iProX | Mon Apr 27 00:00:00 BST 2026

REPOSITORIES: iProX

ACCESS DATA

Json Xml

Similar Datasets

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

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

RNA-seq of human midbrain organoid models of Parkinson's Disease

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

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

Transcriptomic analysis of the midbrain in A53T alpha-synuclein transgenic mice and Myriocin-treated model

Project description:Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of α-synuclein aggregates, yet no disease-modifying therapies currently exist. Ceramide metabolism is increasingly implicated in protein aggregation and mitochondrial dysfunction, both of which are prevalent in neurodegenerative disorders. While prior studies using cell lines have hinted at ceramide's role in PD, the in vivo relevance and therapeutic efficacy of inhibiting its synthesis remained largely unexplored. We aimed to evaluate the therapeutic potential of inhibiting ceramide synthesis in various models of PD, including the A53T α-synuclein transgenic mouse model, primary neurons from patients with PD, and patient-derived midbrain organoids. We found that inhibiting de novo ceramide biosynthesis decreases α-synuclein aggregation and improves motor and cognitive function in A53T α-synuclein transgenic mice, a well-established PD model. Treatment with myriocin, a serine palmitoyltransferase inhibitor, restored mitochondrial morphology, enhanced mitophagy, and reduced neuroinflammation. Single-nucleus transcriptomic analysis revealed that myriocin normalized gene networks related to synaptic transmission, mitochondrial homeostasis, and inflammation. Additionally, human midbrain organoids derived from PD patient-induced pluripotent stem cells exhibited reduced α-synuclein aggregation and preserved dopaminergic neurons following myriocin treatment. Together, these results suggest that targeting ceramide synthesis is a promising strategy for addressing protein aggregation and neuronal death in PD.

2026-02-25 | GSE298956 | GEO

Monitoring α-synuclein ubiquitination dynamics reveals key endosomal effectors mediating its trafficking and degradation

Project description:While defective α-synuclein homeostasis is central to the pathogenesis of Parkinson’s, fundamental questions about its intracellular trafficking remain unresolved. We have developed a bimolecular fluorescence complementation assay in living cells to monitor de novo ubiquitination of α-synuclein. We identified lysine residues 45, 58 and 60 as critical ubiquitination sites for the degradation of α-synuclein. This is mediated by NBR1 binding to ubiquitinated α-synuclein and entry into endosomes in a process that involves ESCRT I-III complexes for subsequent lysosomal degradation. Autophagy or the autophagic chaperone Hsc70 are dispensable for this pathway. Antibodies against diglycine-modified α-synuclein peptides confirmed that endogenous α-synuclein is similarly ubiquitinated in brain and targeted to the lysosome in rat primary and human iPSC-derived neurons. Ubiquitinated α-synuclein was detected in Lewy bodies and cellular models of aggregation suggesting that it may be entrapped with endo/lysosomes in inclusion bodies. Collectively, our data elucidate the intracellular trafficking of de novo ubiquitinated α-synuclein and provide the tools for investigating the rapidly turned-over fraction of this disease-causing protein.

2023-05-17 | PXD038364 | Pride

Bulk-RNA of MACS isolated Microglia from a Parkinson Mouse Model brain from young and old mice and Parkinson and Control

Project description:Microglia are increasingly recognized as active drivers of Parkinson's disease (PD), contributing to neuroinflammation, α-synuclein clearance, and dopaminergic neuron loss. Because aging is the strongest risk factor for PD and independently shifts microglia toward a primed, pro-inflammatory state, disentangling age- and disease-related transcriptional programs is essential. Aim and workflow This dataset profiles the bulk transcriptome of microglia from [PD model] and control mice at [young] and [old] ages (2×2 design) to resolve disease, age, and interaction effects. Brains were enzymatically dissociated, microglia isolated by MACS using CD11b MicroBeads, and total RNA extracted for bulk RNA-seq library preparation and sequencing on Novaseq 6000. n = 3-4 per group. Both sexes included. All samples except Sample1 includes two mice. Sequencing was done with a target of 40G per sample PE150.

2026-06-17 | E-MTAB-17136 | biostudies-arrayexpress

Voluntary exercise alleviates neural functional deficits in Parkinson’s disease mice by inhibiting microglial ferroptosis via SLC7A11/ALOX12 axis

Project description:Microglia are more susceptible to ferroptosis compared to neurons and astrocytes, which may compromise their phagocytic and clearance capabilities of α-synuclein (α-syn) in Parkinson’s disease (PD). While the beneficial effects of physical exercise (PE) on reducing α-syn deposition in PD have been highlighted, the role of PE in modulating microglial ferroptosis remains unclear. This study focuses on the impact of exercise on inhibiting microglial ferroptosis and mitigating α-syn accumulation. We demonstrate that voluntary exercise effectively inhibits microglial ferroptosis. Mechanistically, PE-induced upregulation of SLC7A11 inhibits microglial ferroptosis by suppressing ALOX12, thereby enhancing microglial phagocytosis and clearance of α-syn, which is paralleled by improvements in neurological function in PD mice. Collectively, these findings not only underscore the critical role of microglial ferroptosis in the pathological progression of PD but also elucidate the molecular mechanism by which PE attenuates microglial ferroptosis via the SLC7A11/ALOX12 axis.

2025-09-29 | GSE309457 | GEO

Parkinson's disease genes VPS35 and EIF4G1 interact genetically and converge on alpha-synuclein

Project description:Parkinson's disease (PD) is a common human neurodegenerative movement disorder. Studies of the genetic forms of PD have helped to reveal disease mechanisms. Functional interactions between some Parkinson's disease (PD) genes, like PINK1 and parkin, have been identified, but whether other ones interact remains elusive. Here we report an unexpected genetic interaction between two PD genes, VPS35 and EIF4G1. We provide evidence that EIF4G1 upregulation causes defects associated with protein misfolding. Expression of a sortilin protein rescues these defects, downstream of VPS35, suggesting a potential role for sortilins in PD. We also show interactions between VPS35, EIF4G1 and alpha-synuclein, a protein with a key role in the pathogenesis of both sporadic and familial PD. We extend our findings from yeast to an animal model and show these interactions are conserved in neurons. We also connect VPS35 impairments to neurodegeneration in alpha-synuclein transgenic mice. Our studies reveal unexpected genetic and functional interactions between two seemingly unrelated PD genes and functionally connect them to alpha-synuclein pathobiology in yeast, worms, and mouse. Finally, we provide a resource of candidate PD genes for future genetic and functional interrogation. Ribosome profiling (RiboSeq) of wild type and VPS35 deletion yeast strains, with or without overexpression of the TIF4631 initiation factor

2014-12-19 | E-GEOD-64304 | biostudies-arrayexpress

Neural cell state modulation by PARK2 and dopaminergic neuroprotection by small molecule Parkin agonism [RNA-Seq]

Project description:Parkin, an E3 ubiquitin ligase encoded by PARK2, plays a key role in both hereditary and sporadic Parkinson’s disease (PD), yet there are no therapies currently available that can target this important pathway. Here, we show that Parkin is critical for successful neuronal differentiation and survival, and we develop small-molecule Parkin agonists that can protect dopaminergic neurons. Upon differentiation of neural progenitor cells, loss of Parkin results in a reduced capacity to maintain neuronal cell state, dopaminergic neuronal phenotypes, and stress resistance. Moreover, Parkin loss disrupted cell morphology and the stability of neurites. Transcriptional and single-cell analyses reveal that Parkin controls critical pathways regulating stem-like cell transitions and is needed for stable neuronal maturation. We also examined the effects of FB231, a small molecule enhancer of Parkin E3 ligase activity, in models of PD. FB231 reduced pathological α-synuclein and enhanced cell survival in human iPSC-derived dopaminergic neurons treated with α-synuclein preformed fibrils. Furthermore, FB231 attenuated α-synuclein pathology and dopaminergic neurodegeneration in a gut α-synuclein murine model of PD. Our findings support that Parkin plays a crucial role in maintaining neuronal homeostasis and that pharmacologic activation of Parkin may be a promising strategy to attenuate neurodegeneration in PD.

2026-07-13 | GSE337982 | 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