MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
复制标题
DOI：
10.1038/sj.cdd.4401788
复制
发表时间：
2006-04
影响因子：
12.4
通讯作者：
Hiroo Yamaguchi;Kosuke Kajitani;Yukihiko Dan;M. Furuichi;M. Ohno;K. Sakumi;Dongchon Kang;Y. Nakabeppu
中科院分区：
文献类型：
--
作者：
Hiroo Yamaguchi;Kosuke Kajitani;Yukihiko Dan;M. Furuichi;M. Ohno;K. Sakumi;Dongchon Kang;Y. Nakabeppu
我们之前报道过，8-氧代鸟嘌呤（8-oxoG）在帕金森病患者黑质多巴胺神经元的细胞质中积累，并且这些神经元中携带氧化嘌呤核苷三磷酸酶活性的MTH1表达增加，从而表明核酸的氧化损伤与多巴胺神经元损失有关。在本研究中，我们发现在给予1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的酪氨酸羟化酶（TH）阳性多巴胺神经元丢失期间，小鼠黑质纹状体系统中细胞DNA和RNA中的8-oxoG水平增加。与野生型小鼠相比，MTH1 缺失小鼠在 MPTP 给药后，线粒体 DNA 中 8-oxoG 的积累更多，同时纹状体中 TH 和多巴胺转运蛋白免疫反应性的降低更显着。因此，我们证明MTH1可以保护多巴胺神经元免受核酸氧化损伤，特别是多巴胺神经元纹状体神经末梢的线粒体DNA。
We previously reported that 8-oxoguanine (8-oxoG) accumulates in the cytoplasm of dopamine neurons in the substantia nigra of patients with Parkinson’s disease and the expression of MTH1 carrying an oxidized purine nucleoside triphosphatase activity increases in these neurons, thus suggesting that oxidative damage in nucleic acids is involved in dopamine neuron loss. In the present study, we found that levels of 8-oxoG in cellular DNA and RNA increased in the mouse nigrostriatal system during the tyrosine hydroxylase (TH)-positive dopamine neuron loss induced by the administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). MTH1-null mice exhibited a greater accumulation of 8-oxoG in mitochondrial DNA accompanied by a more significant decrease in TH and dopamine transporter immunoreactivities in the striatum after MPTP administration, than in wild-type mice. We thus demonstrated that MTH1 protects the dopamine neurons from oxidative damage in the nucleic acids, especially in the mitochondrial DNA of striatal nerve terminals of dopamine neurons.