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
Department of Neurology and National Center for Neurological Diseases, Huashan Hospital, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Science. 2025 Feb 21;387(6736):892-900. doi: 10.1126/science.adp3645. Epub 2025 Feb 20.
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 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.
病理性α-突触核蛋白（α-syn）原纤维的神经元积累和扩散是帕金森病（PD）病理生理学中的关键事件。然而，α-syn原纤维摄取的神经元机制仍不清楚。在这项研究中，我们鉴定出FAM171A2作为一个影响α-syn聚集的PD风险基因。过表达FAM171A2会促进α-syn原纤维的内吞作用，并加剧α-syn病理的传播和神经毒性。神经元特异性敲低FAM171A2的表达具有保护作用。从机制上讲，FAM171A2的胞外结构域1通过静电力与α-syn的C末端相互作用，对原纤维的选择性高出1000倍以上。此外，我们通过体外结合试验、细胞模型和小鼠实验，确定苯西替尼是FAM171A2-α-syn原纤维相互作用的有效阻断剂。我们的研究结果确定FAM171A2是α-syn原纤维神经元摄取的潜在受体，因此是抗PD的治疗靶点。
