日本的一項(xiàng)新研究發(fā)現(xiàn),，細(xì)胞內(nèi)的線(xiàn)粒體質(zhì)量下降時(shí)，與帕金森氏癥有關(guān)的一種基因會(huì)出現(xiàn)“自我磷酸化”現(xiàn)象,。了解這一機(jī)制有望促進(jìn)青年型帕金森氏癥的早期發(fā)現(xiàn)和治療,。
東京都醫(yī)學(xué)綜合研究所8月22日發(fā)表公報(bào)說(shuō),，其研究人員發(fā)現(xiàn)，人體正常的“PINK1”基因在線(xiàn)粒體出現(xiàn)異常時(shí)會(huì)被激活,，與磷酸結(jié)合,，出現(xiàn)“自我磷酸化”現(xiàn)象，然后將信號(hào)傳遞給“Parkin”基因,，后者負(fù)責(zé)將異常線(xiàn)粒體分解,。
但在青年型帕金森氏癥患者體內(nèi)，“PINK1”基因無(wú)法與磷酸結(jié)合,，“自我磷酸化”現(xiàn)象停止,，因此無(wú)法傳遞信號(hào)，不能啟動(dòng)異常線(xiàn)粒體分解進(jìn)程,。這種異常狀況與青年型帕金森氏癥的起因相關(guān),。
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(shí)就會(huì)患上帕金森氏癥,。
研究人員指出，這兩種基因之間互動(dòng)的分子機(jī)制一直不明,。此次,，研究小組在分子級(jí)別揭示了“PINK1”基因傳遞信號(hào)的機(jī)制。
研究小組認(rèn)為,，其他類(lèi)型的帕金森氏癥很可能也有類(lèi)似病因,，這一成果有望為開(kāi)發(fā)早期發(fā)現(xiàn)和治療帕金森氏癥的新方法作出貢獻(xiàn)。
帕金森氏癥患者會(huì)出現(xiàn)手腳震顫等運(yùn)動(dòng)障礙,，給患者的日常生活造成很大困難,。目前，日本國(guó)內(nèi)有將近15萬(wàn)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
PMC:
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.
