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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.
摘要：
病理性α-突触核蛋白（α-syn）在细胞间传播，在某种程度上,通过与淋巴细胞激活基因3（Lag3）结合。在这里，我们报道了淀粉样蛋白β前体样蛋白1（Aplp1）与Lag3相互作用，促进结合，内化，传输,和病理性α-syn的毒性。Aplp1和Lag3的缺失消除了多巴胺能神经元的丢失和伴随的由α-syn预制原纤维（PFF）引起的行为缺陷。抗Lag3通过破坏Aplp1和Lag3的相互作用来防止α-synPFF的内化，并在体内阻断α-synPFF诱导的神经变性。Aplp1的鉴定以及与Lag3对α-synPFF诱导病理的相互作用加深了我们对病理性α-syn细胞间传递的分子机制的认识，并为旨在预防帕金森病和相关α-突触核蛋白病的神经变性的治疗策略提供了额外的目标。
