新功能、新界面、新体验,扫描即可下载生物谷APP!
首页 » 帕金森病 » Biochem J:保护大脑抵抗帕金森氏病的关键化学信使

Biochem J:保护大脑抵抗帕金森氏病的关键化学信使

来源:生物谷 2014-03-29 23:15

2014年3月29日讯 /生物谷BIOON/--近日,Dundee大学科学家发现一种新的化学信使,对于保护大脑抵抗帕金森氏病是关键的。Miratul Muqit博士领导的研究小组此前曾发现,两个基因(PINK1和Parkin)的突变导致帕金森氏症。

现在,他们已经取得了完全出乎意料的发现,即两个基因之间的相互作用的方式,他们认为这可能打开令人振奋的研究帕金森的新途径,提供新的药物靶标。他们的研究结果发表在Biochemical Journal杂志。

Muqit博士说:了解在帕金森中脑细胞如何死亡的基本机制,为如何看待这个进展性疾病障碍提供了新的见解。我们以前的研究已经揭示了当PINK1和Parkin基因突变打乱导致帕金森氏病时,涉及PINK1和Parkin基因的重要途径,但我们仍然不明白这些途径是如何被控制的分子细节。

我们的新的研究表明一种化学信使--磷酸泛素,是保护性的,在遗传突变PINK1帕金森氏症患者中不能生成,这使得他们的大脑细胞容易受到应激,引发细胞死亡。Muqit博士研究小组已经发现,PINK1和Parkin基因编码保护脑细胞的重要酶。PINK1和Parkin突变患者中,这些酶的保护作用丧失,脑细胞控制运动被破坏,导致帕金森氏。

以前的工作表明,PINK1酶可通过切换开启Parkin保护脑细胞的存活,但这种情况如何发生是未知的。现在,他们已经知道了两个基因之间是如何相互作用。他们已经发现了PINK1酶的作用,是产生一种新颖的化学信使分子“磷酸泛素”。研究证实磷酸泛素发挥开启Parkin酶的功能。

这项研究为今后的研究开辟了新的令人兴奋的方向,包括研究是否磷酸泛素分子水平低是一个共同的特点和帕金森的诱因,新的数据也表明,有可能开发出药物通过模拟磷酸泛素切换开启帕金酶,以更好地治疗帕金森氏。

这项研究的合著者Dario Alessi教授补充说,现在,我们已经确定了这个新的化学信使,这将是重要的,以确定其在帕金森氏症患者的作用。虽然还有很多工作要做,但我们的研究结果表明,设计药物模拟磷酸泛素,可能是一种新的方法来开发新药物治疗帕金森氏症患者。

研究人员表示:研究发现在帕金森中重要的两个关键蛋白之间的“缺失环节”。我们早已经知道PINK1和Parkin蛋白携手保护那些在帕金森氏中缺失的珍贵脑细胞,但我们不知道是其中机制。这项新研究首次揭示PINK1产生重要化学信使“磷酸泛素”,这是对开启Parkin蛋白的保护作用是必不可少的。(生物谷Bioon.com)

 

doi:10.1042/BJ20140334
Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Serine65

Kazlauskaite A, Kondapalli C, Gourlay R, Campbell DG, Ritorto MS, Hofmann K, Alessi DR, Knebel A, Trost M, Muqit MM.

We have previously reported that the Parkinson's disease associated PINK1 kinase is activated by mitochondrial depolarisation and stimulates the Parkin E3 ligase by phosphorylating Serine65 (Ser65) within its ubiquitin like (Ubl) domain. Using phosphoproteomic analysis, we identified a novel ubiquitin phosphopeptide phosphorylated at Ser65 that was enriched 14-fold in HEK293 cells overexpressing wild type PINK1 stimulated with the mitochondrial uncoupling agent, CCCP, to activate PINK1, compared to cells expressing kinase-inactive PINK1. Ser65 in ubiquitin lies in a similar motif to Ser65 in Parkin's Ubl domain. Remarkably, PINK1 directly phosphorylates Ser65 of ubiquitin in vitro. We undertook a series of experiments that provide striking evidence that Ser65-phosphorylated ubiquitin (ubiquitinPhospho-Ser65) functions as a critical activator of Parkin. Firstly, we demonstrate that a fragment of Parkin lacking the Ubl domain encompassing the Ser65 residue (ΔUbl-Parkin), is robustly activated by ubiquitinPhospho-Ser65, but not by non-phosphorylated ubiquitin. Secondly, we find that the isolated Parkin Ubl domain phosphorylated at Ser65 (UblPhospho-Ser65) can also activate ΔUbl-Parkin similarly to ubiquitinPhospho-Ser65. Thirdly, we establish that ubiquitinPhospho-Ser65 but not non-phosphorylated ubiquitin or UblPhospho-Ser65 activates full-length wild type Parkin as well as the non-phosphorylatable Ser65Ala Parkin mutant. Fourthly, we provide evidence that optimal activation of full-length Parkin E3 ligase is dependent on PINK1 mediated phosphorylation of both Parkin at Ser65 and ubiquitin at Ser65, since only mutation of both proteins at Ser65 completely abolishes Parkin activation. In conclusion, our findings reveal that PINK1 controls Parkin E3 ligase activity not only by phosphorylating Parkin at Ser65 but also by phosphorylating ubiquitin at Ser65. We propose that phosphorylation of Parkin at Ser65 serves to prime the E3 ligase enzyme for activation by ubiquitinPhospho-Ser65, suggesting that small molecules that mimic ubiquitinPhospho-Ser65 could hold promise as novel therapies for Parkinson's.

温馨提示:87%用户都在生物谷APP上阅读,扫描立刻下载! 天天精彩!


相关标签

最新会议 培训班 期刊库