日本研究人員日前宣布,，體內兩種基因變異,，導致線粒體“次品”在細胞內堆積,，是造成青年型帕金森氏癥發(fā)病的原因。
帕金森氏癥患者會出現(xiàn)手腳震顫等運動障礙,，給患者的日常生活造成很大困難,。目前，日本國內有將近15萬名患者,，其中大半是老年病人,，但其中也有10％左右是40歲以前發(fā)病的所謂青年型帕金森氏癥患者。
此前的研究表明,，如果“Parkin”和“PINK1”這兩種基因出現(xiàn)變異,，人在年輕時期就會患上帕金森氏癥。
東京都臨床醫(yī)學綜合研究所與順天堂大學的研究人員共同研究了上述兩種基因,。他們發(fā)現(xiàn),，兩種基因合作負責維持細胞內生產能量的線粒體的功能。在正常情況下,，“PINK1”負責選出異常線粒體,，而“Parkin”負責將其清除。但如果基因出現(xiàn)變異,，導致合作機制被破壞,，異常線粒體就會在神經(jīng)細胞內堆積。異常線粒體不僅無法產生能量,，還會生成有害的活性氧,，異常線粒體的堆積對神經(jīng)細胞來說是雙重打擊。神經(jīng)細胞由此受損甚至死亡，進而導致發(fā)病,。
東京都臨床醫(yī)學綜合研究所首席研究員松田憲之認為：“如果能夠開發(fā)出促進排除異常線粒體的藥物,，將有助于帕金森氏癥的治療。”
這一研究成果已經(jīng)刊登在日前出版的美國《細胞生物學雜志》上,。(生物谷Bioon.com)
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生物谷推薦原文出處：
JCB doi: 10.1083/jcb.200910140
PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy
Noriyuki Matsuda1, Shigeto Sato2, Kahori Shiba3, Kei Okatsu1, Keiko Saisho1, Clement A. Gautier4, Yu-shin Sou1, Shinji Saiki2, Sumihiro Kawajiri2, Fumiaki Sato3, Mayumi Kimura1, Masaaki Komatsu1,5, Nobutaka Hattori2, and Keiji Tanaka1
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.
