Up-regulation of hMUTYH, a DNA repair enzyme, in the mitochondria of substantia nigra in Parkinson's disease
Up-regulation of hMUTYH, a DNA repair enzyme, in the mitochondria of substantia nigra in Parkinson's disease
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DOI：
10.1007/s00401-006-0081-9
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发表时间：
2006-08-01
影响因子：
12.7
通讯作者：
Hattori, Nobutaka
中科院分区：
文献类型：
--
作者：
Arai, Takeo;Fukae, Jiro;Hattori, Nobutaka
有充分的证据表明，氧化应激参与了帕金森病（PD）的线粒体DNA损伤和修复机制。人MutY同源物（hMUTYH）在复制后功能中去除DNA中错误掺入的腺嘌呤相对的8-oxoG，并且定位于细胞核和线粒体中。我们假设hMUTYH参与PD的疾病过程。为了验证我们的假设，我们对PD患者和对照组患者的大脑进行了免疫组织化学和生化研究。我们的研究结果表明，在PD患者的SN的线粒体中的hMUTYH的上调。蛋白质印迹分析还揭示了PD患者中高水平的hMUTYH和脑中47-kDa分子作为主要同种型的表达。该分子定位于线粒体内，如通过用线粒体标记物双重染色所证实的。为了证实这种分子的存在，我们检测了翻译为47-kDa分子的亚型的mRNA。基于mRNA的量，主要分子是α 4。有趣的是，这种分子缺乏线粒体靶向序列。我们的研究结果表明，hMUTYH可能是一个有用的氧化应激的标志物，氧化应激和基因组的不稳定性是重要的PD疾病的过程。
There is ample evidence for the involvement of oxidative stress in mitochondrial DNA damage and repair mechanisms in Parkinson's disease (PD). The human MutY homolog (hMUTYH) which removes misincorporated adenine opposite 8-oxoG in DNA functions in post-replication, and is localized in the nuclei and mitochondria. We hypothesized that hMUTYH is involved in the disease process of PD. To test our hypothesis, we performed immunohistochemical and biochemical studies on brains of patients with PD and those of control patients. Our results showed up-regulation of hMUTYH in the mitochondria of the SN of PD patients. Western blot analysis also revealed high hMUTYH levels in PD patients and expression of a 47-kDa molecule in the brains as the major isoform. This molecule was localized within the mitochondria as confirmed by double staining with a mitochondrial marker. To confirm the presence of this molecule, we examined the mRNAs of isoforms that translate to the 47-kDa molecule. Based on the amount of mRNAs, the major molecule was alpha 4. Interestingly, this molecule lacks the mitochondria targeting sequence. Our results suggest that hMUTYH might be a useful marker of oxidative stress and that oxidative stress and genomic instability are important in the PD disease process.