iProXProteomicsYunlong YangHomo Sapienshttp://www.iprox.org/page/project.html?id=IPX0016863000yunlongyang@fudan.edu.cnFudan UniversityiProXfalseCholesterol enhances lysosome-autophagosome fusion for better α-synuclein clearance in GBA L444P mutated Parkinson’s diseaseMutations 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.Mon Apr 27 00:00:00 BST 2026PXD0776869606