LRRK2 and the Endolysosomal System in Parkinson's Disease.
LRRK2 and the Endolysosomal System in Parkinson's Disease.
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DOI：
10.3233/jpd-202138
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Moore DJ
中科院分区：
文献类型：
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作者：
Erb ML;Moore DJ
富含亮氨酸的重复蛋白激酶2(LRRK2)基因突变导致常染色体显性遗传性家族性帕金森病(PD)，致病突变增强LRRK2激酶活性。越来越多的证据表明，LRRK2在家族性和散发性帕金森病的神经元损伤和病理中起作用，这使得人们对了解帕金森病背后的分子通路特别感兴趣。尽管到目前为止LRRK2已经得到了广泛的研究，但我们对LRRK2在整个细胞中看似不同的功能的理解仍然不完整。在这篇综述中，我们讨论了LRRK2在内切酶途径中的功能。内吞作用、囊泡运输途径和溶酶体降解通常在许多神经退行性疾病中被破坏，包括帕金森病。此外，许多PD相关基因产物在这些交叉通路中发挥作用，提示内溶酶体系统在维持PD的蛋白质稳态和神经元健康方面发挥着重要作用。LRRK2活性可以调节突触小泡的内吞作用、溶酶体功能、高尔基体网络的维持和分选、囊泡的运输和自噬，而LRRK2激酶活性的变化则根据不同的细胞类型或模型系统而破坏或调节这些途径。LRRK2受溶酶体内至少两种蛋白Rab29和VPS35的调控，这两种蛋白可能是LRRK2激酶活性的主要调节因子。研究LRRK2在不同帕金森病模型，特别是体内模型中的作用和调控，将有助于深入了解帕金森病的细胞和分子病理生理机制，以及LRRK2是否可以作为治疗家族性和散发性帕金森病的有效药物靶点。
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant familial Parkinson’s disease (PD), with pathogenic mutations enhancing LRRK2 kinase activity. There is a growing body of evidence indicating that LRRK2 contributes to neuronal damage and pathology both in familial and sporadic PD, making it of particular interest for understanding the molecular pathways that underlie PD. Although LRRK2 has been extensively studied to date, our understanding of the seemingly diverse functions of LRRK2 throughout the cell remains incomplete. In this review, we discuss the functions of LRRK2 within the endolysosomal pathway. Endocytosis, vesicle trafficking pathways, and lysosomal degradation are commonly disrupted in many neurodegenerative diseases, including PD. Additionally, many PD-linked gene products function in these intersecting pathways, suggesting an important role for the endolysosomal system in maintaining protein homeostasis and neuronal health in PD. LRRK2 activity can regulate synaptic vesicle endocytosis, lysosomal function, Golgi network maintenance and sorting, vesicular trafficking and autophagy, with alterations in LRRK2 kinase activity serving to disrupt or regulate these pathways depending on the distinct cell type or model system. LRRK2 is critically regulated by at least two proteins in the endolysosomal pathway, Rab29 and VPS35, which may serve as master regulators of LRRK2 kinase activity. Investigating the function and regulation of LRRK2 in the endolysosomal pathway in diverse PD models, especially in vivo models, will provide critical insight into the cellular and molecular pathophysiological mechanisms driving PD and whether LRRK2 represents a viable drug target for disease-modification in familial and sporadic PD.