{"title":"神经元 FAM171A2 介导α-突触核蛋白纤维摄取并驱动帕金森病。","authors":"Kai-Min Wu, Qian-Hui Xu, Yi-Qi Liu, Yi-Wei Feng, Si-Da Han, Ya-Ru Zhang, Shi-Dong Chen, Yu Guo, Bang-Sheng Wu, Ling-Zhi Ma, Yi Zhang, Yi-Lin Chen, Liu Yang, Zhao-Fei Yang, Yu-Jie Xiao, Ting-Ting Wang, Jue Zhao, Shu-Fen Chen, Mei Cui, Bo-Xun Lu, Wei-Dong Le, You-Sheng Shu, Keqiang Ye, Jia-Yi Li, Wen-Sheng Li, Jian Wang, Cong Liu, Peng Yuan, Jin-Tai Yu","doi":"10.1126/science.adp3645","DOIUrl":null,"url":null,"abstract":"<p><p>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 <i>FAM171A2</i> 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.</p>","PeriodicalId":21678,"journal":{"name":"Science","volume":"387 6736","pages":"892-900"},"PeriodicalIF":44.7000,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease.\",\"authors\":\"Kai-Min Wu, Qian-Hui Xu, Yi-Qi Liu, Yi-Wei Feng, Si-Da Han, Ya-Ru Zhang, Shi-Dong Chen, Yu Guo, Bang-Sheng Wu, Ling-Zhi Ma, Yi Zhang, Yi-Lin Chen, Liu Yang, Zhao-Fei Yang, Yu-Jie Xiao, Ting-Ting Wang, Jue Zhao, Shu-Fen Chen, Mei Cui, Bo-Xun Lu, Wei-Dong Le, You-Sheng Shu, Keqiang Ye, Jia-Yi Li, Wen-Sheng Li, Jian Wang, Cong Liu, Peng Yuan, Jin-Tai Yu\",\"doi\":\"10.1126/science.adp3645\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 <i>FAM171A2</i> 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.</p>\",\"PeriodicalId\":21678,\"journal\":{\"name\":\"Science\",\"volume\":\"387 6736\",\"pages\":\"892-900\"},\"PeriodicalIF\":44.7000,\"publicationDate\":\"2025-02-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1126/science.adp3645\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/2/20 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1126/science.adp3645","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/2/20 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease.
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.
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