Authors
Mingjia Chen, Fengtao Liu, Yujie Yang, Ruibo Chen, Linhua Gan, Yimin Sun, Yuchen Yan, Sisi Xie, Chenwei Zhu, Xiaoting Sun, Yang Li, Shun Zhu, Wen Liu, Ji Zuo, Yunlong Yang, Jian Wang
Published in
Cell reports. Volume 45. Issue 8. Pages 117800. Aug 06, 2026. Epub Aug 06, 2026.
Abstract
Mutations in lysosomal enzyme glucocerebrosidase (GBA), the most common genetic risk factor for Parkinson disease (PD), exacerbate α-synuclein pathology through unclear mechanisms. Here, we report, in a large cohort, that GBA-mutated PD patients exhibit lower serum cholesterol levels. By introducing the most common GBA variant in our cohort, L444P, into human α-synuclein knock-in mice, we noted that the mice exhibited behavioral and molecular pathological PD features at 12 months of age. Mechanistically, lysosomal proteomics identified the loss of lysosome-cytoplasmic vesicle interactions and cholesterol-containing lipid microdomains in both PD patients and mice. Autophagic flux monitoring revealed impaired autophagosome-lysosome fusion in GbaL444P/+ neurons. Gain- and loss-of-function experiments uncovered cholesterol synthesis impairment via glycosphingolipid-reduced SREBP2 levels. Importantly, cholesterol supplementation was found to enhance the autophagic flux and mitigate α-synuclein accumulation in vitro, whereas AAV-Srebp2 delivery increased α-synuclein clearance in GbaL444P/+ mice. Our study provides animal models and mechanistic insights into GBA-associated PD and offers a therapeutic paradigm by facilitating cholesterol-associated α-synuclein autophagic clearance.
PMID:
42560815
Bibliographic data and abstract were imported from PubMed on 07 Aug 2026.
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