{"database":"iProX","file_versions":[],"scores":null,"additional":{"omics_type":["Proteomics"],"submitter":["Yunlong Yang"],"species":["Homo Sapiens"],"full_dataset_link":["http://www.iprox.org/page/project.html?id=IPX0016863000"],"submitter_email":["yunlongyang@fudan.edu.cn"],"submitter_affiliation":["Fudan University"],"sample_protocol":[""],"repository":["iProX"],"data_protocol":[""],"additional_accession":[]},"is_claimable":false,"name":"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.","dates":{"publication":"Mon Apr 27 00:00:00 BST 2026"},"accession":"PXD077686","cross_references":{"TAXONOMY":["9606"]}}