帕金森病 z-bio 2025-03-05 257

　Figure FAM171A2 promotes the occurrence and development mechanism of Parkinson's disease

　　With the support of National Natural Science Foundation projects (approval numbers: 82271471, 82401676, 92249305), Professor Yu Jintai's team from Huashan Hospital affiliated with Fudan University, together with Professor Yuan Peng's team from the Institute of Brain Science Translational Research at Fudan University and Professor Liu Cong's team from the Interdisciplinary Research Center of Biology and Chemistry at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, have made progress in the study of the pathogenesis of Parkinson's disease. The research results, titled "Neuronal FAM171A2 mediates alpha synuclein fiber uptake and drives Parkinson's disease", were published online on February 20, 2025 in the journal Science. The paper link is: https://www.science.org/doi/10.1126/science.adp3645 .

　　Parkinson's disease (PD) is the second most common neurodegenerative disease, with a prevalence rate of 1.7% among the elderly population aged 65 and above in China. By 2030, the number of Parkinson's disease patients in China is expected to reach 5 million, accounting for almost half of the global patient population. Previous studies have found that alpha synuclein can misfold and aggregate under pathological conditions to form pathological alpha synuclein, which destroys neuronal function and leads to its death. It is a key pathogenic protein in PD. These pathogenic proteins will also spread like "seeds", invading neighboring neurons, recruiting alpha synuclein monomers within neurons to undergo misfolding, forming more pathogenic "seeds". These pathogenic "seeds" can spread between neurons, and when they reach the substantia nigra region of the midbrain, they can lead to the death of dopaminergic neurons, resulting in PD motor symptoms such as bradykinesia, resting tremor, and muscle rigidity. However, the mechanism of pathological alpha synuclein transmission between neurons is still unclear, and effective intervention methods are still lacking in clinical practice.

　　The research team first conducted genome-wide association analysis on a large population and found that FAM171A2 is a PD risk gene; Based on clinical sample analysis of PD patients, it was found that the content of FAM171A2 protein in the brain of patients increased, and the higher the FAM171A2 content, the higher the pathological alpha synuclein content in the brain. Further research has found that FAM171A2 can selectively bind to pathological alpha synuclein on the neuronal cell membrane and carry it into neurons, inducing misfolding of monomeric alpha synuclein within neurons, resulting in neuronal death and its spread between neurons. The team subsequently confirmed through research that knocking out FAM171A2 on mouse neurons can effectively control the progression of Parkinson's like symptoms in mice. Based on the aforementioned findings, the research team utilized artificial intelligence's protein structure prediction and virtual screening techniques to successfully screen candidate small molecule becentinib from over 7000 drugs. In vitro and animal experiments confirmed that this small molecule can effectively inhibit the binding of FAM171A2 protein to pathological alpha synuclein and inhibit the uptake of pathological alpha synuclein by dopaminergic neurons (Figure).

　　This study discovered the potential membrane receptor FAM171A2 protein of pathological alpha synuclein on neurons, revealing that FAM171A2 protein is the key to promoting the spread of pathological alpha synuclein. The effective inhibitor of FAM171A2, becentib, was screened as a candidate small molecule for the treatment of PD. The research findings provide potential new targets and ideas for the treatment of PD.