2. Academic Validation
  3. Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease

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

  • Science. 2025 Feb 21;387(6736):892-900. doi: 10.1126/science.adp3645.
Kai-Min Wu 1,  Qian-Hui Xu 2 3,  Yi-Qi Liu 1,  Yi-Wei Feng 1,  Si-Da Han 1,  Ya-Ru Zhang 1,  Shi-Dong Chen 1,  Yu Guo 1,  Bang-Sheng Wu 1,  Ling-Zhi Ma 4,  Yi Zhang 1,  Yi-Lin Chen 1,  Liu Yang 1,  Zhao-Fei Yang 5,  Yu-Jie Xiao 6,  Ting-Ting Wang 7,  Jue Zhao 1,  Shu-Fen Chen 1,  Mei Cui 1,  Bo-Xun Lu 8,  Wei-Dong Le 5 9,  You-Sheng Shu 6,  Keqiang Ye 10 11,  Jia-Yi Li 12 13,  Wen-Sheng Li 14,  Jian Wang 1,  Cong Liu 2 15 16,  Peng Yuan 1 17,  Jin-Tai Yu 1
Affiliations

Affiliations

  • 1 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.
  • 2 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 3 University of Chinese Academy of Sciences, Beijing, China.
  • 4 Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.
  • 5 Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
  • 6 Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
  • 7 Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China.
  • 8 Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, School of Life Sciences, Fudan University, Shanghai, China.
  • 9 Institute of Neurology, Sichuan Provincial People's Hospital, Medical School of University of Electronic Science and Technology of China, Chengdu, China.
  • 10 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
  • 11 Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
  • 12 Neural Plasticity and Repair Unit, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
  • 13 Institute of Health Sciences, China Medical University, Liaoning, Shenyang, China.
  • 14 Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
  • 15 State Key Laboratory of Small Molecule Modulation of Biological Processes, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, China.
  • 16 Shanghai Academy of Natural Sciences (SANS), Fudan University, Shanghai, China.
  • 17 Department of Rehabilitation Medicine, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai, China.
PMID: 39977508 DOI: 10.1126/science.adp3645
Abstract

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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