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 <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.
Authors
- Jin‐Tai Yu (ORCID: https://orcid.org/0000-0002-7686-0547)
- Zhaofei Yang (ORCID: https://orcid.org/0000-0003-4165-5567)
- Boxun Lu (ORCID: https://orcid.org/0000-0002-1675-9340)
- Yujie Xiao (ORCID: https://orcid.org/0000-0002-9200-656X)
- Weidong Le (ORCID: https://orcid.org/0000-0001-7459-2705)
- Lingzhi Ma (ORCID: https://orcid.org/0000-0001-8963-0030)
- Shu-Fen Chen (ORCID: https://orcid.org/0000-0003-4161-1433)
- Mei Cui (ORCID: https://orcid.org/0000-0002-6449-8106)
- Yu Guo
- Yiqi Liu (ORCID: https://orcid.org/0000-0002-2488-9356)
- Peng Yuan (ORCID: https://orcid.org/0000-0003-4051-4447)
- Shi-Dong Chen (ORCID: https://orcid.org/0000-0002-1114-622X)
- Qianhui Xu (ORCID: https://orcid.org/0000-0001-9677-2897)
- Jue Zhao (ORCID: https://orcid.org/0000-0002-1035-1790)
- Keqiang Ye (ORCID: https://orcid.org/0000-0002-7657-8154)
- Sida Han
- Bang‐Sheng Wu (ORCID: https://orcid.org/0000-0002-8807-6354)
- Kaimin Wu (ORCID: https://orcid.org/0000-0002-3307-6306)
- Cong Liu (ORCID: https://orcid.org/0000-0003-3425-6672)
- Jian Wang (ORCID: https://orcid.org/0000-0002-2748-395X)
- Yi Zhang (ORCID: https://orcid.org/0000-0002-8228-2560)
- Yilin Chen (ORCID: https://orcid.org/0000-0003-0040-3881)
- Jiayi Li (ORCID: https://orcid.org/0000-0002-7770-7376)
- Ya-Ru Zhang
- Yang Liu (ORCID: https://orcid.org/0000-0002-0972-8511)
- Wensheng Li (ORCID: https://orcid.org/0000-0003-4160-9317)
- Yiwei Feng
- Yousheng Shu
- Tingting Wang (ORCID: https://orcid.org/0000-0001-5288-2314)
Institutions
- Qingdao University (CN)
- Shanghai Academy of Social Sciences (CN)
- Shanghai Medical College of Fudan University (CN)
- University of Electronic Science and Technology of China (CN)
- Emory University (US)
- Lund University (SE)
- Dalian Medical University (CN)
- Chinese Academy of Sciences (CN)
- Fudan University (CN)
- Shanghai Institute of Organic Chemistry (CN)
- Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (CN)
- Qingdao Municipal Hospital (CN)
- First Affiliated Hospital of Dalian Medical University (CN)
- Shenzhen Institutes of Advanced Technology (CN)
- Huashan Hospital (CN)
- University of Chinese Academy of Sciences (CN)
- State Key Laboratory of Medical Neurobiology
- China Medical University (CN)
Publication Details
- Journal
- Science
- Published
- 2025-02-20
- DOI
- https://doi.org/10.1126/science.adp3645
- Citations
- 47
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 65.30