日本的一项新研究发现，细胞内的线粒体质量下降时，与帕金森氏症有关的一种基因会出现“自我磷酸化”现象。了解这一机制有望促进青年型帕金森氏症的早期发现和治疗。
东京都医学综合研究所8月22日发表公报说，其研究人员发现，人体正常的“PINK1”基因在线粒体出现异常时会被激活，与磷酸结合，出现“自我磷酸化”现象，然后将信号传递给“Parkin”基因，后者负责将异常线粒体分解。
但在青年型帕金森氏症患者体内，“PINK1”基因无法与磷酸结合，“自我磷酸化”现象停止，因此无法传递信号，不能启动异常线粒体分解进程。这种异常状况与青年型帕金森氏症的起因相关。
此前的研究表明，如果“Parkin”和“PINK1”这两种基因出现变异，人在年轻时就会患上帕金森氏症。
研究人员指出，这两种基因之间互动的分子机制一直不明。此次，研究小组在分子级别揭示了“PINK1”基因传递信号的机制。
研究小组认为，其他类型的帕金森氏症很可能也有类似病因，这一成果有望为开发早期发现和治疗帕金森氏症的新方法作出贡献。
帕金森氏症患者会出现手脚震颤等运动障碍，给患者的日常生活造成很大困难。目前，日本国内有将近15万名患者，其中大多是老年人，但也有10%左右是40岁以前发病的青年型帕金森氏症患者。（生物谷Bioon.com）
doi:10.1038/ncomms2016
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PINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria
Kei Okatsu, Toshihiko Oka, Masahiro Iguchi, Kenji Imamura, Hidetaka Kosako, Naoki Tani, Mayumi Kimura, Etsu Go, Fumika Koyano, Manabu Funayama, Kahori Shiba-Fukushima, Shigeto Sato, Hideaki Shimizu, Yuko Fukunaga, Hisaaki Taniguchi, Masaaki Komatsu, Nobutaka Hattori, Katsuyoshi Mihara, Keiji Tanaka1 & Noriyuki Matsuda1
Dysfunction of PINK1, a mitochondrial Ser/Thr kinase, causes familial Parkinson's disease (PD). Recent studies have revealed that PINK1 is rapidly degraded in healthy mitochondria but accumulates on the membrane potential (ΔΨm)-deficient mitochondria, where it recruits another familial PD gene product, Parkin, to ubiquitylate the damaged mitochondria. Despite extensive study, the mechanism underlying the homeostatic control of PINK1 remains unknown. Here we report that PINK1 is autophosphorylated following a decrease in ΔΨm and that most disease-relevant mutations hinder this event. Mass spectrometric and mutational analyses demonstrate that PINK1 autophosphorylation occurs at Ser228 and Ser402, residues that are structurally clustered together. Importantly, Ala mutation of these sites abolishes autophosphorylation of PINK1 and inhibits Parkin recruitment onto depolarized mitochondria, whereas Asp (phosphorylation-mimic) mutation promotes mitochondrial localization of Parkin even though autophosphorylation was still compromised. We propose that autophosphorylation of Ser228 and Ser402 in PINK1 is essential for efficient mitochondrial localization of Parkin.
