The Ubiquitin Project, Tokyo Metropolitan Institute of Medical Science, Room N-202, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
The Ubiquitin Project, Tokyo Metropolitan Institute of Medical Science, Room N-202, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
Neurosci Res. 2020 Oct;159:16-24. doi: 10.1016/j.neures.2020.03.009. Epub 2020 Mar 19.
In 1998, PARKIN was reported as a causal gene for hereditary recessive Parkinsonism by Kitada, Mizuno, Hattori, and Shimizu et al. Later in 2004, PINK1 was also reported as a causal gene for hereditary recessive Parkinsonism by Valente, Auburger, and Wood et al. Although many unsolved mysteries still remain, our knowledge of PINK1 and Parkin function has increased dramatically since then. Despite a number of milestone studies that advanced the PINK1 and Parkin research field, a critical turning point was undoubtedly the determination that their genuine subcellular localization was on depolarized mitochondria. In this review, we outline the key studies that have contributed to our current model for mitochondrial localization of PINK1 and Parkin. Interestingly, like two sides of a coin, our attempts to elucidate the mechanisms underlying the localization of PINK1 and Parkin were inextricably tied to the identification of the PINK1 substrate and molecular dissection of the Parkin activation mechanism.
1998 年，Kitada、Mizuno、Hattori 和 Shimizu 等人报道 PARKIN 是遗传性隐性帕金森病的致病基因。后来，在 2004 年，Valente、Auburger 和 Wood 等人也报道 PINK1 是遗传性隐性帕金森病的致病基因。尽管仍有许多未解之谜，但自那时以来，我们对 PINK1 和 Parkin 功能的了解已经有了显著的提高。尽管有许多里程碑式的研究推动了 PINK1 和 Parkin 研究领域的发展，但一个关键的转折点无疑是确定它们真正的亚细胞定位是在去极化的线粒体上。在这篇综述中，我们概述了对我们目前的 PINK1 和 Parkin 线粒体定位模型有贡献的关键研究。有趣的是，就像一枚硬币的两面，我们对 PINK1 和 Parkin 定位机制的阐明的尝试与 PINK1 底物的鉴定以及 Parkin 激活机制的分子剖析紧密相关。
