Point mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD) and are implicated in a significant proportion of apparently sporadic PD cases. Clinically, LRRK2-driven PD is indistinguishable from sporadic PD, making it an attractive genetic model for the much more common sporadic PD. In this review, we highlight recent advances in understanding LRRK2's subcellular functions using LRRK2-driven PD models, while also considering some of the limitations of these model systems. Recent developments of particular importance include new evidence of key LRRK2 functions in the endolysosomal system and LRRK2’s regulation of and by Rab GTPases. Additionally, LRRK2's interaction with the cytoskeleton allowed elucidation of the LRRK2 structure and appears relevant to LRRK2 protein degradation and LRRK2 inhibitor therapies. We further discuss how LRRK2's interactions with other PD-driving genes, such as the VPS35, GBA1, and SNCA genes, may highlight cellular pathways more broadly disrupted in PD.

中文翻译：

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LRRK2 在帕金森病中的细胞生物学

富含亮氨酸重复激酶 2 (LRRK2) 的点突变是家族性帕金森病 (PD) 的最常见原因，并且与很大一部分明显散发的 PD 病例有关。临床上，LRRK2 驱动的帕金森病与散发性帕金森病没有区别，这使其成为更常见的散发性帕金森病的有吸引力的遗传模型。在这篇综述中，我们重点介绍了使用 LRRK2 驱动的 PD 模型了解 LRRK2 亚细胞功能的最新进展，同时也考虑了这些模型系统的一些局限性。最近特别重要的进展包括 LRRK2 在内溶酶体系统中关键功能的新证据以及 LRRK2 对 Rab GTPases 的调节。此外，LRRK2 与细胞骨架的相互作用可以阐明 LRRK2 结构，并且似乎与 LRRK2 蛋白降解和 LRRK2 抑制剂治疗相关。我们进一步讨论 LRRK2 如何与其他 PD 驱动基因（例如VPS35、GBA1和SNCA基因可能突显 PD 中更广泛破坏的细胞通路。