Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.

Mao X, Gu H, Kim D, Kimura Y, Wang N, Xu E, Kumbhar R, Ming X, Wang H, Chen C, Zhang S, Jia C, Liu Y, Bian H, Karuppagounder SS, Akkentli F, Chen Q, Jia L, Hwang H, Lee SH, Ke X, Chang M, Li A, Yang J, Rastegar C, Sriparna M, Ge P, Brahmachari S, Kim S, Zhang S, Shimoda Y, Saar M, Liu H, Kweon SH, Ying M, Workman CJ, Vignali DAA, Muller UC, Liu C, Ko HS, Dawson VL, Dawson TM.

Nat Commun · 2024-05-31

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Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid β precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson's disease and related α-synucleinopathies.

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