日本的一項新研究發(fā)現(xiàn)，細胞內(nèi)的線粒體質(zhì)量下降時,，與帕金森氏癥有關的一種基因會出現(xiàn)“自我磷酸化”現(xiàn)象,。了解這一機制有望促進青年型帕金森氏癥的早期發(fā)現(xiàn)和治療。
東京都醫(yī)學綜合研究所8月22日發(fā)表公報說,，其研究人員發(fā)現(xiàn),，人體正常的“PINK1”基因在線粒體出現(xiàn)異常時會被激活,，與磷酸結合，出現(xiàn)“自我磷酸化”現(xiàn)象,，然后將信號傳遞給“Parkin”基因,，后者負責將異常線粒體分解。
但在青年型帕金森氏癥患者體內(nèi),，“PINK1”基因無法與磷酸結合,，“自我磷酸化”現(xiàn)象停止，因此無法傳遞信號,，不能啟動異常線粒體分解進程,。這種異常狀況與青年型帕金森氏癥的起因相關。
此前的研究表明,，如果“Parkin”和“PINK1”這兩種基因出現(xiàn)變異,，人在年輕時就會患上帕金森氏癥。
研究人員指出,，這兩種基因之間互動的分子機制一直不明,。此次，研究小組在分子級別揭示了“PINK1”基因傳遞信號的機制,。
研究小組認為,，其他類型的帕金森氏癥很可能也有類似病因，這一成果有望為開發(fā)早期發(fā)現(xiàn)和治療帕金森氏癥的新方法作出貢獻,。
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(nèi)有將近15萬名患者,，其中大多是老年人，但也有10%左右是40歲以前發(fā)病的青年型帕金森氏癥患者,。（生物谷Bioon.com）
doi:10.1038/ncomms2016
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PMID:
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.
