DJ-1-binding compounds prevent oxidative stress-induced cell death and movement defect in Parkinson's disease model rats
DJ-1-binding compounds prevent oxidative stress-induced cell death and movement defect in Parkinson's disease model rats
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DOI：
10.1111/j.1471-4159.2008.05327.x
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发表时间：
2008-06-01
影响因子：
4.7
通讯作者：
Ariga, Hiroyoshi
中科院分区：
文献类型：
--
作者：
Miyazaki, Shin;Yanagida, Takashi;Ariga, Hiroyoshi
帕金森病（PD）是由神经元细胞死亡引起的。虽然多巴胺的前体和多巴胺降解的抑制剂已用于PD治疗，但在治疗期间细胞死亡仍在发展。DJ-1是PD家族形式PARK 7的致病基因产物，在转录调节和抗氧化应激中起作用，其功能的丧失被认为导致PD的发作。在DJ-1的氨基酸106（C106）处的半胱氨酸的超氧化使得DJ-1失活，并且已经在具有散发形式的PD的患者中观察到这种氧化的DJ-1。在这项研究中，我们通过虚拟筛选分离出与C106区域结合的化合物。这些化合物阻止氧化应激诱导的SH-SY 5 Y细胞、胚胎干细胞衍生的多巴胺能细胞和腹侧中脑的原代神经元细胞的死亡，但不阻止DJ-1敲低的SH-SY 5 Y细胞和NIH 3 T3细胞的死亡，表明化合物的作用对DJ-1是特异性的。这些化合物抑制活性氧的产生，并恢复线粒体复合物I和酪氨酸羟化酶的活性，这已被氧化应激损害。这些化合物阻止了黑质中多巴胺能细胞的死亡，并恢复了6-羟基多巴胺注射的PD模型大鼠的运动异常。这些化合物的作用机制之一是防止DJ-1的过度氧化，并且化合物在体外通过血脑屏障。总之，这些结果表明，这些化合物应该成为PD治疗的基础药物。
Parkinson's disease (PD) is caused by neuronal cell death. Although a precursor of dopamine and inhibitors of dopamine degradation have been used for PD therapy, cell death progresses during treatment. DJ-1, a causative gene product of a familial form of PD, PARK7, plays roles in transcriptional regulation and anti-oxidative stress, and loss of its function is thought to result in the onset of PD. Superfluous oxidation of cysteine at amino acid 106 (C106) of DJ-1 renders DJ-1 inactive, and such oxidized DJ-1 has been observed in patients with the sporadic form of PD. In this study, we isolated compounds that bind to the region at C106 by a virtual screening. These compounds prevented oxidative stress-induced death of SH-SY5Y cells, embryonic stem cell-derived dopaminergic cells and primary neuronal cells of the ventral mesencephalon, but not that of DJ-1-knockdown cells of SH-SY5Y and NIH3T3 cells, indicating that the effect of the compounds is specific to DJ-1. These compounds inhibited production of reactive oxygen species and restored activities of mitochondrial complex I and tyrosine hydroxylase that had been compromised by oxidative stress. These compounds prevented dopaminergic cell death in the substantia nigra and restored movement abnormality in 6-hydroxyldopamine-injected PD model rats. One mechanism of action of these compounds is prevention of superfluous oxidation of DJ-1, and the compounds passed through the blood-brain barrier in vitro. Taken together, the results indicate that these compounds should become fundamental drugs for PD therapy.