Autosomal dominant missense mutations that hyperactivate the leucine-rich repeat protein kinase-2 (LRRK2) are a common cause of inherited Parkinson's disease and therapeutic efficacy of LRRK2 inhibitors is being tested in clinical trials. In this review, we discuss the nuts and bolts of our current understanding of how the LRRK2 is misregulated by mutations and how pathway activity is affected by LRRK2 binding to membrane, microtubule filaments, and 14-3-3, as well as by upstream components such as Rab29 and VPS35. We discuss recent work that points toward a subset of Rab proteins comprising key physiological substrates that bind new sets of effectors, such as RILPL1/2, JIP3 and JIP4 after phosphorylation by LRRK2. We explore what is known about how LRRK2 regulates ciliogenesis, the endosomal-lysosomal system, immune responses and interplay with alpha-synuclein and tau and how this might be linked to Parkinson's' disease.

中文翻译：

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阐明富含亮氨酸重复蛋白激酶 2 在正常细胞和帕金森病中的功能的进展。

常染色体显性错义突变使富含亮氨酸的重复蛋白激酶 2 (LRRK2) 过度激活，是遗传性帕金森病的常见原因，LRRK2 抑制剂的治疗效果正在临床试验中进行测试。在这篇综述中，我们讨论了我们目前对 LRRK2 如何被突变错误调节以及 LRRK2 与膜、微管丝和 14-3-3 结合以及上游成分如何影响通路活性的理解的具体细节例如 Rab29 和 VPS35。我们讨论了最近的研究，该研究指向 Rab 蛋白的一个子集，其中包含与新的效应子集结合的关键生理底物，例如被 LRRK2 磷酸化后的 RILPL1/2、JIP3 和 JIP4。我们探索 LRRK2 如何调节纤毛发生、内体-溶酶体系统、免疫反应以及与 α-突触核蛋白和 tau 蛋白的相互作用，以及这如何与帕金森病相关。