Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson’s disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle trafficking, likely by Rab phosphorylation, that in turn may regulate different aspects of neuronal physiology. Here we show that LRRK2 interacts with Sec8, one of eight subunits of the exocyst complex. The exocyst complex is an evolutionarily conserved multisubunit protein complex mainly involved in tethering secretory vesicles to the plasma membrane and implicated in the regulation of multiple biological processes modulated by vesicle trafficking. Interestingly, Rabs and exocyst complex belong to the same protein network. Our experimental evidence indicates that LRRK2 kinase activity or the presence of the LRRK2 kinase domain regulate the assembly of exocyst subunits and that the over-expression of Sec8 significantly rescues the LRRK2 G2019S mutant pathological effect. Our findings strongly suggest an interesting molecular mechanism by which LRRK2 could modulate vesicle trafficking and may have important implications to decode the complex role that LRRK2 plays in neuronal physiology.

中文翻译：

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LRRK2 通过与 Sec8 相互作用调节胞外囊复合体组装


LRRK2 突变在家族性和散发性帕金森病 (PD) 中发挥着关键作用。迄今为止，LRRK2 在 PD 发病和进展中的作用仍然很大程度上未知。然而，实验证据强调了 LRRK2 在控制囊泡运输中的关键作用，可能是通过 Rab 磷酸化，进而调节神经元生理学的不同方面。在这里，我们展示了 LRRK2 与 Sec8 相互作用，Sec8 是外囊复合体的八个亚基之一。外囊复合物是一种进化上保守的多亚基蛋白复合物，主要参与将分泌囊泡束缚到质膜上，并参与囊泡运输调节的多种生物过程的调节。有趣的是，Rab 和外囊复合体属于同一蛋白质网络。我们的实验证据表明，LRRK2 激酶活性或 LRRK2 激酶结构域的存在调节外囊亚基的组装，并且 Sec8 的过表达显着挽救了 LRRK2 G2019S 突变体的病理效应。我们的研究结果强烈表明了一种有趣的分子机制，LRRK2 可以通过该机制调节囊泡运输，并且可能对解码 LRRK2 在神经元生理学中发挥的复杂作用具有重要意义。