Cholesterol enhances lysosome-autophagosome fusion for better α-synuclein clearance in GBA L444P-mutated Parkinson disease.
Cholesterol enhances lysosome-autophagosome fusion for better α-synuclein clearance in GBA L444P-mutated Parkinson disease.
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Huashan, CN · Author affiliation
Department of Neurology, National Research Center for Aging and Medicine, National Center for Neurological Disorders, and State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai 200040, China; Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing 100070, China.Location evidence
Shanghai, CN · Author affiliation
Department of Neurology, National Research Center for Aging and Medicine, National Center for Neurological Disorders, and State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai 200040, China; Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing 100070, China.Location evidence
Beijing, CN · Author affiliation
Department of Neurology, National Research Center for Aging and Medicine, National Center for Neurological Disorders, and State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai 200040, China; Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing 100070, China.Location evidence
Longyan, CN · Author affiliation
Department of Cardiology, Basic Scientific Research Center, Longyan First Hospital Affiliated to Fujian Medical University, Longyan 364000, Fujian Province, China.Location evidence
Wenzhou, CN · Author affiliation
School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325024, Zhejiang Province, China.Location evidence
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Original 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.