In vivo complementation of complex I by the yeast Ndi1 enzyme -: Possible application for treatment of Parkinson disease
In vivo complementation of complex I by the yeast Ndi1 enzyme -: Possible application for treatment of Parkinson disease
复制标题
DOI：
10.1074/jbc.m600922200
复制
发表时间：
2006-05-19
影响因子：
4.8
通讯作者：
Yagi, Takao
中科院分区：
文献类型：
--
作者：
Seo, Byoung Boo;Nakamaru-Ogiso, Eiko;Yagi, Takao
最近的研究表明，NADH-醌氧化还原酶（复合物I）的功能障碍与许多人类疾病有关，包括神经退行性疾病，如帕金森病。我们以前已经表明，单亚基rote-no-sensitive NADH-醌氧化还原酶（NdI 1）的酿酒酵母线粒体可以恢复NADH氧化在复杂的I-缺陷的哺乳动物细胞。Ndi 1酶对复合物I抑制剂不敏感，如鱼藤酮和1-甲基-4-苯基吡啶离子，已知为1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）的代谢物。为了测试NDI 1基因作为体内治疗剂的可能用途，我们选择了帕金森病的小鼠模型。将NDI 1重组腺相关病毒颗粒（rAAV-NDI 1）单侧注射到小鼠黑质中。然后用MPTP对动物进行处理。黑质纹状体系统的神经变性程度通过酪氨酸羟化酶和胶质细胞酸性蛋白的分析进行化学评估。很明显，用于注射rAAV-NDI 1的一侧的黑质神经元保留了高水平的酪氨酸羟化酶阳性细胞，并且同侧纹状体的去神经支配明显少于对侧纹状体。此外，接受rAAV-NDI 1的半球中多巴胺及其代谢物的纹状体浓度显著高于未治疗的半球，达到正常水平的50%以上。这些结果表明，表达的NdI 1蛋白增强了对MPTP诱导的神经元损伤的抵抗。本研究是第一次成功的证明，在动物中的NdI 1酶的复合物I的互补。
Recent studies suggest that dysfunction of the NADH-quinone oxidoreductase (complex I) is associated with a number of human diseases, including neurodegenerative disorders such as Parkinson disease. We have shown previously that the single subunit rote-none-insensitive NADH-quinone oxidoreductase (NdI1) of Saccharomyces cerevisiae mitochondria can restore NADH oxidation in complex I-deficient mammalian cells. The Ndi1 enzyme is insensitive to complex I inhibitors such as rotenone and 1-methyl-4-phenylpyridinium ion, known as a metabolite of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). To test the possible use of the NDI1 gene as a therapeutic agent in vivo, we chose amouse model of Parkinson disease. The NDI1-recombinant adeno-associated virus particles (rAAV-NDI1) were injected unilaterally into the substantia nigra of mice. The animals were then subjected to treatment with MPTP. The degree of neurodegeneration in the nigrostriatal system was assessed immunohistochemically through the analysis of tyrosine hydroxylase and glial fibrillary acidic protein. It was evident that the substantia nigra neurons on the side used for injection of rAAV-NDI1 retained a high level of tyrosine hydroxylase-positive cells, and the ipsilateral striatum exhibited significantly less denervation than the contralateral striatum. Furthermore, striatal concentrations of dopamine and its metabolites in the hemisphere that received rAAV-NDI1 were substantially higher than those of the untreated hemisphere, reaching more than 50% of the normal levels. These results indicate that the expressed NdI1 protein elicits resistance to MPTP-induced neuronal injury. The present study is the first successful demonstration of complementation of complex I by the NdI1 enzyme in animals.