Aplp1 and the Aplp1-Lag3 Complex facilitates transmission of pathologic alpha-synuclein

Mao, X.; Gu, H.; Kim, D.; Kimura, Y.; Wang, N.; Xu, E.; Chen, C.; Zhang, S.; Jia, C.; Liu, Y.; Bian, H.; Karuppagounder, S.; Jia, L.; Ke, X.; Chang, M.; Lee, A.; Yang, J.; Rastegar, C.; Sriparna, M.; Ge, P.; Brahmachari, S.; Kim, S.; Shimoda, Y.; Saar, M.; Workman, C.; Vignali, D.; Muller, U.; Liu, C.; Ko, H.; Dawson, V.; Dawson, T.

doi:10.1101/2021.05.01.442157

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bioRxiv · 10.1101/2021.05.01.442157

Aplp1 and the Aplp1-Lag3 Complex facilitates transmission of pathologic alpha-synuclein

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Abstract

Pathologic -synuclein (-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid {beta} precursor-like protein 1 (Aplp1) forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic -syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by -syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of -syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by -syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for -syn PFF induced pathology advances our understanding of the molecular mechanism of cell-to-cell transmission of pathologic -syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinsons disease and related -synucleinopathies. One Sentence SummaryAplp1 forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic -synuclein. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/442157v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1d746bforg.highwire.dtl.DTLVardef@65acb2org.highwire.dtl.DTLVardef@12cf2f0org.highwire.dtl.DTLVardef@19d6e_HPS_FORMAT_FIGEXP M_FIG Aplp1 and the Aplp1-Lag3 complex facilitates transmission of pathologic -synuclein. Aplp1 is a receptor that drives pathologic -syn transmission, and genetic depletion of Aplp1 can significantly reduce the -synuclein pathogenesis. Aplp1 and Lag3 forms an Aplp1-Lag3 complex that accounts for substantial binding of pathologic -syn to cortical neurons. Together Aplp1 and Lag3 play a major role in pathologic -syn internalization, transmission and toxicity. Double knockout of Aplp1 and Lag3 and or a Lag3 antibody that disrupts the Aplp1 and Lag3 complex almost completely blocks -syn PFF-induced neurodegeneration. C_FIG

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Mao, X., Gu, H., Kim, D., Kimura, Y., Wang, N., Xu, E., Chen, C., Zhang, S., Jia, C., Liu, Y., Bian, H., Karuppagounder, S., Jia, L., Ke, X., Chang, M., Lee, A., Yang, J., Rastegar, C., Sriparna, M., Ge, P., Brahmachari, S., Kim, S., Shimoda, Y., Saar, M., Workman, C., Vignali, D., Muller, U., Liu, C., Ko, H., Dawson, V., Dawson, T.. 2021-05-01. Aplp1 and the Aplp1-Lag3 Complex facilitates transmission of pathologic alpha-synuclein. https://doi.org/10.1101/2021.05.01.442157

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