%0 Journal Article
%T Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.
%A Mao X
%A Gu H
%A Kim D
%A Kimura Y
%A Wang N
%A Xu E
%A Kumbhar R
%A Ming X
%A Wang H
%A Chen C
%A Zhang S
%A Jia C
%A Liu Y
%A Bian H
%A Karuppagounder SS
%A Akkentli F
%A Chen Q
%A Jia L
%A Hwang H
%A Lee SH
%A Ke X
%A Chang M
%A Li A
%A Yang J
%A Rastegar C
%A Sriparna M
%A Ge P
%A Brahmachari S
%A Kim S
%A Zhang S
%A Shimoda Y
%A Saar M
%A Liu H
%A Kweon SH
%A Ying M
%A Workman CJ
%A Vignali DAA
%A Muller UC
%A Liu C
%A Ko HS
%A Dawson VL
%A Dawson TM
%J Nat Commun
%V 15
%N 1
%D 2024 May 31
%M 38821932
%F 17.694
%R 10.1038/s41467-024-49016-3
%X 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.