Recent genetic evidence revealed endocytic pathway plays a major role in Parkinsons disease (PD). However, the molecular mechanism is poorly understood. Here we report that LRRK2, the most genetic cause of PD, binds to and phosphorylates AP2M1, the core component of endocytosis recently implicated in PD risk. Both knockout and overexpression of LRRK2 cause abnormal AP2M1 phosphorylation cycle and in turn endocytic defects. Mechanistically, knockout of LRRK2 decreases AP2M1 phosphorylation required for the initial clathrin coated vesicle (CCV) formation while LRRK2 overexpression inhibits AP2M1 uncoating for entering into a new cycle of CCV formation. Our study also uncovered a novel tissue-specific regulation of AP2M1 phosphorylation by LRRK2. Further, we found LRRK2 phosphorylation on AP2M1 mediates LRRK2-induced neuronal toxicity both in vitro and in vivo. Importantly, AP2M1 phosphorylation levels are elevated in PD patient fibroblasts. Together, our study provides a direct mechanistic link between LRRK2, AP2 and endocytosis in PD pathogenesis.

中文翻译：

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LRRK2调节AP2M1磷酸化周期，以介导内吞作用和多巴胺能神经退行性变

最近的遗传证据表明，内吞途径在帕金森病（PD）中起主要作用。但是，对分子机理的了解很少。在这里我们报道，PD的最遗传原因LRRK2结合并磷酸化AP2M1，AP2M1是最近与PD风险相关的内吞作用的核心成分。LRRK2的敲除和过表达均会导致异常的AP2M1磷酸化周期，进而引起内吞缺陷。从机制上讲，敲除LRRK2会减少最初的网格蛋白包被小泡（CCV）形成所需的AP2M1磷酸化，而LRRK2的过表达会抑制AP2M1的脱膜进入新的CCV形成周期。我们的研究还发现了LRRK2对AP2M1磷酸化的新型组织特异性调控。进一步，我们发现AP2M1上的LRRK2磷酸化在体外和体内介导LRRK2诱导的神经元毒性。重要的是，PD患者成纤维细胞中AP2M1的磷酸化水平升高。总之，我们的研究提供了LRRK2，AP2与PD发病机制中的内吞作用之间的直接机制联系。