Aplp1 interacts with Lag3 to facilitates transmission of pathologic α-synuclein

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 advances our understanding of the molecular mechanism 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., , , # Aplp1 interacts with Lag3 to facilitates transmission of pathologic α-synuclein

[https://doi.org/10.5061/dryad.5hqbzkhcw](https://doi.org/10.5061/dryad.5hqbzkhcw)

**Brief summary of the dataset contents:**

In this study, we investigated the role of amyloid precursor-like protein 1 (Aplp1) and lymphocyte activation gene 3 (Lag3) in the binding, internalization, and progression of pathological alpha-synuclein (α-syn) preformed fibrils (PFFs). Through a combination of in vitro cell culture models, structural biology techniques, and in vivo PD mouse models, we studied their roles in mediating the transmission and pathogenesis of pathological α-synuclein.

We performed α-syn PFF binding assays in various cell lines transfected with Aplp1, Lag3, or their deletion mutants. Internalization assays were performed using fluorescently labeled α-syn PFFs in primary cortical neuron cultures from wild-type, Aplp1 knockout, Lag3 knockout, and Aplp1/Lag3 double knockout mice. Using mouse primary ne...