Kuwahara Tomoki, Iwatsubo Takeshi
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Front Neurosci. 2020 Mar 18;14:227. doi: 10.3389/fnins.2020.00227. eCollection 2020.
The leucine-rich repeat kinase 2 (), the most common causative gene for autosomal-dominant familial Parkinson's disease, encodes a large protein kinase harboring multiple characteristic domains. LRRK2 phosphorylates a set of Rab GTPases in cells, which is enhanced by the Parkinson-associated LRRK2 mutations. Accumulating evidence suggests that LRRK2 regulates intracellular vesicle trafficking and organelle maintenance including Golgi, endosomes and lysosomes. Furthermore, genetic knockout or inhibition of LRRK2 cause lysosomal abnormalities in rodents and primates, and cells from Parkinson's patients with LRRK2 mutations also exhibit altered lysosome morphology. Cell biological studies on LRRK2 in a diverse cellular context further strengthen the potential connection between LRRK2 and regulation of the endolysosomal system, part of which is mediated by Rab phosphorylation by LRRK2. We will focus on the latest advances on the role of LRRK2 and Rab in relation to the endolysosomal system, and discuss the possible link to the pathomechanism of Parkinson's disease.
富含亮氨酸重复激酶2（LRRK2）是常染色体显性遗传性帕金森病最常见的致病基因，编码一种含有多个特征结构域的大型蛋白激酶。LRRK2在细胞中使一组Rab GTP酶磷酸化，帕金森病相关的LRRK2突变会增强这种磷酸化作用。越来越多的证据表明，LRRK2调节细胞内囊泡运输和细胞器维持，包括高尔基体、内体和溶酶体。此外，基因敲除或抑制LRRK2会在啮齿动物和灵长类动物中导致溶酶体异常，携带LRRK2突变的帕金森病患者的细胞也表现出溶酶体形态改变。在不同细胞环境中对LRRK2进行的细胞生物学研究进一步强化了LRRK2与内溶酶体系统调节之间的潜在联系，其中部分联系是由LRRK2对Rab的磷酸化介导的。我们将重点关注LRRK2和Rab在与内溶酶体系统相关方面作用的最新进展，并讨论其与帕金森病发病机制的可能联系。
