Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease

• 成果类型: Article
• 署名作者: Wu, Kai-Min; Xu, Qian-Hui; Liu, Yi-Qi; Feng, Yi-Wei; Han, Si-Da; Zhang, Ya-Ru; Chen, Shi-Dong; Guo, Yu; Wu, Bang-Sheng; Ma, Ling-Zhi; Zhang, Yi; Chen, Yi-Lin; Yang, Liu; Yang, Zhao-Fei; Xiao, Yu-Jie; Wang, Ting-Ting; Zhao, Jue; Chen, Shu-Fen; Cui, Mei; Lu, Bo-Xun; Le, Wei-Dong; Shu, You-Sheng; Ye, Keqiang; Li, Jia-Yi; Li, Wen-Sheng; Wang, Jian; Liu, Cong; Yuan, Peng; Yu, Jin-Tai
• 署名单位: Fudan University; Fudan University; Fudan University; Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Qingdao University; Qingdao Municipal Hospital; Dalian Medical University; Fudan University; Fudan University; Fudan University; Fudan University; University of Electronic Science & Technology of China; Sichuan Provincial People's Hospital; Emory University; Chinese Academy of Sciences; Shenzhen Institute of Advanced Technology, CAS; Lund University; China Medical University; Fudan University; Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS; University of Chinese Academy of Sciences, CAS; Fudan University; Fudan University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11375
• DOI: 10.1126/science.adp3645
• 发表日期: 2025-02-21
• 页码: 892-900
• 关键词: lewy body; vulnerability; transmission; pathology; SPREAD

摘要

Neuronal accumulation and spread of pathological alpha-synuclein (alpha-syn) fibrils are key events in Parkinson's disease (PD) pathophysiology. However, the neuronal mechanisms underlying the uptake of alpha-syn fibrils remain unclear. In this work, we identified FAM171A2 as a PD risk gene that affects alpha-syn aggregation. Overexpressing FAM171A2 promotes alpha-syn fibril endocytosis and exacerbates the spread and neurotoxicity of alpha-syn pathology. Neuronal-specific knockdown of FAM171A2 expression shows protective effects. Mechanistically, the FAM171A2 extracellular domain 1 interacts with the alpha-syn C terminus through electrostatic forces, with >1000 times more selective for fibrils. Furthermore, we identified bemcentinib as an effective blocker of FAM171A2-alpha-syn fibril interaction with an in vitro binding assay, in cellular models, and in mice. Our findings identified FAM171A2 as a potential receptor for the neuronal uptake of alpha-syn fibrils and, thus, as a therapeutic target against PD.