{Reference Type}: Journal Article
{Title}: Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.
{Author}: 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;
{Journal}: Nat Commun
{Volume}: 15
{Issue}: 1
{Year}: 2024 May 31
{Factor}: 17.694
{DOI}: 10.1038/s41467-024-49016-3
{Abstract}: 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.