Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06030, USA.
Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA.
Trends Mol Med. 2024 Oct;30(10):982-996. doi: 10.1016/j.molmed.2024.07.003. Epub 2024 Aug 16.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of Parkinson's disease (PD) to date. Dysfunction in LRRK2 enzymatic activities and elevated protein levels are associated with the disease. How is LRRK2 activated, and what downstream molecular and cellular processes does LRRK2 regulate? Addressing these questions is crucial to decipher the disease mechanisms. In this review we focus on the upstream regulations and briefly discuss downstream substrates of LRRK2 as well as the cellular consequences caused by these regulations. Building on these basic findings, we discuss therapeutic strategies targeting LRRK2 and highlight the challenges in clinical trials. We further highlight the important questions that remains to be answered in the LRRK2 field.
LRRK2 基因突变是迄今为止帕金森病 (PD) 最常见的原因。LRRK2 酶活性的功能障碍和蛋白水平的升高与该疾病有关。LRRK2 如何被激活，以及它调节哪些下游分子和细胞过程？解决这些问题对于破译疾病机制至关重要。在这篇综述中，我们重点关注 LRRK2 的上游调控，并简要讨论 LRRK2 的下游底物以及这些调控所导致的细胞后果。在此基础上，我们讨论了针对 LRRK2 的治疗策略，并强调了临床试验中的挑战。我们还强调了 LRRK2 领域仍需回答的重要问题。
