Parkin&PINK1两基因合作负责线粒体产能

日本研究人员日前宣布，体内两种基因变异，导致线粒体“次品”在细胞内堆积，是造成青年型帕金森氏症发病的原因。

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，其中大半是老年病人，但其中也有10％左右是40岁以前发病的所谓青年型帕金森氏症患者。

此前的研究表明，如果“Parkin”和“PINK1”这两种基因出现变异，人在年轻时期就会患上帕金森氏症。

东京都临床医学综合研究所与顺天堂大学的研究人员共同研究了上述两种基因。他们发现，两种基因合作负责维持细胞内生产能量的线粒体的功能。在正常情况下，“PINK1”负责选出异常线粒体，而“Parkin”负责将其清除。但如果基因出现变异，导致合作机制被破坏，异常线粒体就会在神经细胞内堆积。异常线粒体不仅无法产生能量，还会生成有害的活性氧，异常线粒体的堆积对神经细胞来说是双重打击。神经细胞由此受损甚至死亡，进而导致发病。

东京都临床医学综合研究所首席研究员松田宪之认为：“如果能够开发出促进排除异常线粒体的药物，将有助于帕金森氏症的治疗。”

这一研究成果已经刊登在日前出版的美国《细胞生物学杂志》上。

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PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged
mitochondria and activates latent Parkin for mitophagy
Noriyuki Matsuda, Shigeto Sato, Kahori Shiba, Kei Okatsu, Keiko Saisho, Clement A. Gautier,
Yu-shin Sou, Shinji Saiki, Sumihiro Kawajiri, Fumiaki Sato, Mayumi Kimura, Masaaki Komatsu,
Nobutaka Hattori, and Keiji Tanaka

Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Recent identification of genes linked to familial forms of PD such as Parkin and PINK1 (PTEN-induced putative kinase 1) has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. However, the exact mechanism underlying the functional interplay between Parkin-catalyzed ubiquitylation and PINK1-regulated mitochondrial quality control remains an enigma. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential–dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. Interestingly, the ubiquitin ligase activity of Parkin is repressed in the cytoplasm under steady-state conditions; however, PINK1-dependent mitochondrial localization liberates the latent enzymatic activity of Parkin. Some pathogenic mutations of PINK1 and Parkin interfere with the aforementioned events, suggesting an etiological importance. These results provide crucial insight into the pathogenic mechanisms of PD.