Familial Parkinson's Disease-Associated L166P Mutant DJ-1 is Cleaved by Mitochondrial Serine Protease Omi/HtrA2
Familial Parkinson's Disease-Associated L166P Mutant DJ-1 is Cleaved by Mitochondrial Serine Protease Omi/HtrA2
复制标题
家族性帕金森病相关 L166P 突变体 DJ-1 被线粒体丝氨酸蛋白酶 Omi/HtrA2 切割
DOI：
10.1007/s12264-017-0196-0
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发表时间：
2017-12-01
影响因子：
5.6
通讯作者：
Ren, Haigang
中科院分区：
文献类型：
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作者：
Fu, Kai;Wang, Yanfei;Ren, Haigang
帕金森病（PD）是最常见的神经退行性运动障碍。DJ-1的突变，包括L166P，是隐性早发性帕金森病的原因。许多证据表明，L166P不仅是一种功能丧失突变体，而且是一种导致线粒体功能障碍的促凋亡样蛋白。据报道，L166P是不稳定的，并且错误定位到线粒体。然而，与野生型DJ-1相比，L166P不稳定性的机制在很大程度上仍然未知。在这里，我们发现Omi/HtrA2，一种线粒体丝氨酸蛋白酶，也与PD的发病机制有关，有助于L166P的不稳定性。Omi直接与线粒体中的L166P相互作用并切割L166P，从而降低L166P水平。然而，Omi没有结合和切割野生型DJ-1。此外，Omi在丝氨酸残基3和121位点切割L166P，而过表达Omi可减轻H2O2处理下L166P诱导的细胞死亡。我们的数据揭示了DJ-1和Omi这两个PD相关遗传因子之间的桥梁，这有助于我们了解PD的发病机制。
Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Mutations in the DJ-1, including L166P, are responsible for recessive early-onset PD. Many lines of evidence have shown that L166P is not only a loss-of-function mutant, but also a pro-apoptotic-like protein that results in mitochondrial dysfunction. L166P has been reported to be unstable and to mislocalize to mitochondria. However, the mechanisms underlying the instability of L166P compared to wild-type DJ-1 remain largely unknown. Here, we showed that Omi/HtrA2, a mitochondrial serine protease that has also been linked to the pathogenesis of PD, contributed to L166P instability. Omi directly interacted with and cleaved L166P in mitochondria to decrease the L166P level. However, Omi did not bind and cleave wild-type DJ-1. Moreover, Omi cleaved L166P at both serine residues 3 and 121, while L166P-induced cell death under H2O2 treatment was alleviated by over-expression of Omi. Our data reveal a bridge between DJ-1 and Omi, two PD-associated genetic factors, which contributes to our understanding of the pathogenesis of PD.