Function of DJ-1, a causative gene for familial Parkinson's disease PARK7

DJ-1最近被证明与家族性帕金森病(PD)Park7的发病有关。我们已经证明DJ-1在转录调节和抗氧化应激中发挥作用，其功能的丧失被认为是触发帕金森病发病的原因。我们和其他人还发现，除了细胞质和细胞核外，一些DJ-1还位于线粒体中，氧化应激刺激DJ-1易位到线粒体。此外，我们发现DJ-1通过与其亚单位结合是线粒体复合体1的正调节因子。将重组DJ-1蛋白注射到PD模型大鼠的大脑中，并注射到左侧黑质6-羟基多巴胺(6-OHDA)，PD的表型，包括黑质和纹状体的多巴胺能神经元死亡，纹状体中多巴胺和多巴胺转运体水平的下降，以及运动异常，被野生型DJ-1显著改善，但不能改善在PD患者中发现的DJ-1的突变形式L166P DJ-1。此外，重组DJ-1还能抑制6-OHDA诱导的SH-SY5Y细胞产生活性氧和细胞死亡。然后我们筛选了与DJ-1催化区域结合的小分子化合物，发现这些化合物通过抑制DJ-1的氧化而保护SH-SY5Y细胞免受氧化应激诱导的细胞死亡。这些发现表明DJ-1及其结合化合物是帕金森病的治疗靶点。

DJ-1 has recently been shown to be responsible for onset of familial Parkinson's disease (PD), PARK7. We have shown that DJ-1 plays roles in transcriptional regulation and anti-oxidative stress, and loss of its function is thought to trigger onset of PD. We and others have also shown that some DJ-1 is located in mitochondria in addition to the cytoplasm and nucleus and that translocation of DJ-1 to mitochondria was stimulated by oxidative stress. Furthermore, we found that DJ-1 was a positive regulator of the mitochondrial complex 1 by binding to its subunit.When a recombinant DJ-1 protein was administrated into the brain of PD model rats that had been injected to 6-hydroxydopamine (6-OHDA) in the left substantia nigra, PD phenotypes, including dopaminergic neuron death both in the substantia nigra and striatum, decrease in dopamine and dopamine transporter levels in the striatum, and motor abnormality, were dramatically improved by wild-type DJ-1 but not L166P DJ-1, a mutant form of DJ-1 found in PD patients. Furthermore, production of reactive oxygen species and cell death induced by 6-OHDA in SH-SY5Y cells were inhibited by addition of the recombinant DJ-1. We then screened low-molecular weight compounds that bind to the catalytic region of DJ-1 and found that these compounds protected SH-SY5Y cells from oxidative stress-induced cell death by inhibiting oxidation of DJ-1.These findings suggest that DJ-1 and its binding compounds are therapeutic targets for PD.