It has been 15 years since the Leucine-rich repeat kinase 2 (LRRK2) gene was identified as the most common genetic cause for Parkinson’s disease (PD). The two most common mutations are the LRRK2-G2019S, located in the kinase domain, and the LRRK2-R1441C, located in the ROC-COR domain. While the LRRK2-G2019S mutation is associated with increased kinase activity, the LRRK2-R1441C exhibits a decreased GTPase activity and altered kinase activity. Multiple lines of evidence have linked the LRRK2 protein with a role in the autophagy pathway and with lysosomal activity in neurons. Neurons rely heavily on autophagy to recycle proteins and process cellular waste due to their post-mitotic state. Additionally, lysosomal activity decreases with age which can potentiate the accumulation of α-synuclein, the pathological hallmark of PD, and subsequently lead to the build-up of Lewy bodies (LBs) observed in this disorder. This review provides an up to date summary of the LRRK2 field to understand its physiological role in the autophagy pathway in neurons and related cells. Careful assessment of how LRRK2 participates in the regulation of phagophore and autophagosome formation, autophagosome and lysosome fusion, lysosomal maturation, maintenance of lysosomal pH and calcium levels, and lysosomal protein degradation are addressed. The autophagy pathway is a complex cellular process and due to the variety of LRRK2 models studied in the field, associated phenotypes have been reported to be seemingly conflicting. This review provides an in-depth discussion of different models to assess the normal and disease-associated role of the LRRK2 protein on autophagic function. Given the importance of the autophagy pathway in Parkinson’s pathogenesis it is particularly relevant to focus on the role of LRRK2 to discover novel therapeutic approaches that restore lysosomal protein degradation homeostasis.

中文翻译：

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“LRRK2：自噬和溶酶体活性”

自从富含亮氨酸重复激酶 2 (LRRK2) 基因被确定为帕金森病 (PD) 最常见的遗传原因以来，已经过去了 15 年。两个最常见的突变是位于激酶域中的 LRRK2-G2019S 和位于 ROC-COR 域中的 LRRK2-R1441C。虽然 LRRK2-G2019S 突变与激酶活性增加有关，但 LRRK2-R1441C 表现出 GTP 酶活性降低和激酶活性改变。多项证据已将 LRRK2 蛋白与自噬途径中的作用和神经元中的溶酶体活性联系起来。由于有丝分裂后的状态，神经元严重依赖自噬来回收蛋白质和处理细胞废物。此外，溶酶体活性随着年龄的增长而降低，这可以增强 α-突触核蛋白的积累，这是 PD 的病理标志，并随后导致在这种疾病中观察到的路易体 (LB) 的积聚。本综述提供了 LRRK2 领域的最新总结，以了解其在神经元和相关细胞自噬途径中的生理作用。仔细评估 LRRK2 如何参与调节吞噬细胞和自噬体形成、自噬体和溶酶体融合、溶酶体成熟、溶酶体 pH 值和钙水平的维持以及溶酶体蛋白质降解。自噬途径是一个复杂的细胞过程，由于该领域研究的 LRRK2 模型多种多样，据报道相关表型似乎相互矛盾。本综述深入讨论了不同模型，以评估 LRRK2 蛋白对自噬功能的正常和疾病相关作用。