Department of Pathology, University of California, San Diego, San Diego, California, USA.
Department of Pathology, University of California, San Diego, San Diego, California, USA
Mol Cell Biol. 2021 Apr 22;41(5). doi: 10.1128/MCB.00660-20.
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 , , and genes, may highlight cellular pathways more broadly disrupted in PD.
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，并且与相当一部分明显散发的 PD 病例有关。临床上，LRRK2 驱动的 PD 与散发的 PD 无法区分，因此它是更常见的散发 PD 的一个有吸引力的遗传模型。在这篇综述中，我们强调了使用 LRRK2 驱动的 PD 模型来理解 LRRK2 的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。最近的重要进展包括关键的 LRRK2 功能在内体溶酶体系统中的新证据，以及 LRRK2 对 Rab GTPases 的调节作用和受 Rab GTPases 的调节作用。此外，LRRK2 与细胞骨架的相互作用使得阐明 LRRK2 结构成为可能，并且与 LRRK2 蛋白降解和 LRRK2 抑制剂治疗相关。我们进一步讨论了 LRRK2 与其他 PD 驱动基因（如 GBA、VPS35 和 DCTN1 基因）的相互作用如何可能突出 PD 中更广泛破坏的细胞途径。
