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

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【Editor’s summary】:

One of the major causes of neurodegeneration in patients with Parkinson’s disease (PD) is the intracellular accumulation of α-synuclein in neurons. Wu et al. investigated the mechanisms mediating the uptake of α-synuclein in neurons using in vitro and in vivo models. The product of the recently identified PD-risk gene FAM171A2 was found to be the neuronal receptor for α-synuclein fibrils, mediating their internalization through endocytosis. In silico screening identified an approved drug, bemcentinib, that is able to inhibit α-synuclein internalization in vitro and in vivo by blocking its binding to FAM171A2. The results provide insights into PD pathogenesis and identify a potential therapeutic target. —Mattia Maroso


【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.


DOI:10.1126/science.adp3645

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