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

作者：Kaimin Wu, Qianhui Xu, Yiqi Liu, Yiwei Feng, Sida Han, Ya-Ru Zhang, Shi-Dong Chen, Yu Guo, Bang‐Sheng Wu, Lingzhi Ma, Yi Zhang, Yilin Chen, Yang Liu, Zhaofei Yang, Yujie Xiao, Tingting Wang, Jue Zhao, Shu-Fen Chen, Mei Cui, Boxun Lu, Weidong Le, Yousheng Shu, Keqiang Ye, Jiayi Li, Wensheng Li, Jian Wang, Cong Liu, Peng Yuan, Jin‐Tai Yu · 发表于：Science · 年份：2025 · DOI：10.1126/science.adp3645 · 被引用次数：71 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Neurological disorders and treatments、Alzheimer's disease research and treatments

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