PXD077686-1

PXD077686 is an original dataset announced via ProteomeXchange.

Title	Cholesterol enhances lysosome-autophagosome fusion for better α-synuclein clearance in GBA L444P mutated Parkinson’s disease
Description	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.
HostingRepository	iProX
AnnounceDate	2026-04-27
AnnouncementXML	Submission_2026-07-12_17:37:26.096.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mingjia Chen
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2026-04-27 18:16:39	ID requested
⏵ 1	2026-07-12 17:37:26	announced

Dataset with its publication pending

submitter keyword: Glucocerebrosidase, Parkinson’s disease, cholesterol, autophagy, mouse model, α-synuclein

Yunlong Yang
contact affiliation	Fudan University
contact email	yunlongyang@fudan.edu.cn
lab head
Mingjia Chen
contact affiliation	Fudan University
contact email	chenmingjia0528@163.com
dataset submitter

iProX dataset URI