Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress
Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress
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DOI：
10.1093/hmg/ddi007
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发表时间：
2005-01-01
影响因子：
3.5
通讯作者：
Dawson, VL
中科院分区：
文献类型：
--
作者：
Moore, DJ;Zhang, L;Dawson, VL
罕见的单基因形式的帕金森病（PD）的鉴定提供了巨大的洞察这种疾病的分子发病机制。α-突触核蛋白、parkin、DJ-1和PINK 1中的遗传性突变导致家族性PD。在更常见的散发性PD中，氧化应激和线粒体复合物-I功能紊乱被认为在疾病发病机制中起重要作用。然而，DJ-1与其他PD连锁基因和氧化应激的关系尚未探讨。在这里，我们表明，致病性突变形式的DJ-1特异性，但差异与帕金，E3泛素连接酶。化学交联显示致病性DJ-1突变体在同源二聚体形成中表现出损伤，这表明帕金可能与单体DJ-1结合。帕金不能特异性地泛素化和增强L166 P和M26 I突变体DJ-1的降解，而是促进它们在培养细胞中的稳定性。parkin与L166 P DJ-1的相互作用可能涉及含有CHIP和Hsp 70的更大的蛋白质复合物，这可能是parkin介导的泛素化缺乏的原因。氧化应激也促进DJ-1和帕金之间的相互作用，但这并不导致DJ-1的泛素化或降解。帕金森病介导的DJ-1蛋白稳定性的改变可能是致病相关的DJ-1水平显着增加，在洗涤剂不溶性部分从散发性PD/DLB脑，但减少在不溶性部分从帕金森连锁常染色体隐性青少年发病PD脑。这些数据可能在多个水平上将DJ-1和parkin在共同的分子途径中联系起来，这可能对理解遗传性和散发性PD的发病机制具有重要意义。
The identification of rare monogenic forms of Parkinson's disease (PD) has provided tremendous insight into the molecular pathogenesis of this disorder. Heritable mutations in alpha-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.