NO. 66
CIMR Wednesday Lecture Series
Time:
Wednesday, Apr. 16 2025, 4:00 p.m.
Location:
Multi-Function Hall, 2nd Floor, North Basic Research Building
Host：
Lin Mei (梅林)
Chinese Institutes for Medical Research, Beijing
Speaker：
Jin-Tai yu (郁金泰)
Professor/Chief Physician
Department of Neurology and National Center for Neurological Diseases, Huashan Hospital
Shanghai Medical College, Fudan University
TITLE：
Parkinson's Disease: Original Innovative Target FAM171A2 and Candidate New Drugs
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.
SELECTED PAPERS
1. Wu KM, Xu QH, Liu YQ, Feng YW, Han SD, Zhang YR, Chen SD, Guo Y, Wu BS, Ma LZ, Zhang Y, Chen YL, Yang L, Yang ZF, Xiao YJ, Wang TT, Zhao J, Chen SF, Cui M, Lu BX, Le WD, Shu YS, Ye K, Li JY, Li WS, Wang J, Liu C, Yuan P, Yu JT. Neuronal FAM171A2 mediates α-synuclein fibril uptake and drives Parkinson's disease. Science. 2025 Feb 21; 387(6736): 892-900.
2. Deng YT, You J, He Y, Zhang Y, Li HY, Wu XR, Cheng JY, Guo Y, Long ZW, Chen YL, Li ZY, Yang L, Zhang YR, Chen SD, Ge YJ, Huang YY, Shi LM, Dong Q, Mao Y, Feng JF, Cheng W, Yu JT. Atlas of the plasma proteome in health and disease in 53,026 adults. Cell. 2025 Jan 9; 188(1): 253-271.e7.
3. Guo Y, You J, Zhang Y, Liu WS, Huang YY, Zhang YR, Zhang W, Dong Q, Feng JF, Cheng W, Yu JT. Plasma proteomic profiles predict future dementia in healthy adults. Nat Aging. 2024 Feb; 4(2): 247-260.
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