DNA Repair Mechanisms Protecting Brain and Neuronal Cells from Damage Caused by Reactive Oxygen Species

DNA 修复机制保护大脑和神经元细胞免受活性氧造成的损伤

基本信息

批准号：
10480218
负责人：
NAKABEPPU Yusaku
金额：
$ 7.55万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

Neuronal precursor cells proliferate during embryonic and early postnatal stage of mammalian development, however they lose their proliferative potential after differentiation into functional neurons. Neurons are expected to survive and function for the entire life of an individual, however, variotus damage accumulated during aging seems to cause their degeneration. Most energy required for neuronal function such as release of neurotransmitters is supplied by oxidative phosphorylation in mitochondria, where reactive oxygen species (ROS) are continuously produced. Thus, neurons are exposed to danger of oxidative damage by ROS, as a consequence of maintenance of their neuronal function.In this project, based on the idea that oxidative damage of DNA and nucleotides are detrimental for maintaining functions of brain and neuronal cells, we have characterized the defense mechanisms against oxidative DNA damage in mammals including humanbeing, that is, sanitization of oxidized nucleotides and … More repair of oxidaized bases in DNA.We have identified three enzymes involved in the processes, oxidized purine nucleoside triphosphatase encoded by MTH1 gene, 2-hydroxyadenine (2-OH-A)/adenine DNA glycosylase encoded by MYH gene, and 8-oxoguanine (8-oxoG) DNA glycosylase encoded by OGG1 gene, and analyzed their functions and regulatory mechanisms for their expression. We demonstrated that the three enzymes are involved in the maintenance of both nuclear and mitochondrial genomes, and further obtained data suggesting that alterations of their expression are involved in the process of neurogerenerative diseases in human.Up to now, it has been accepted that DNA damage in brain or neuronal cells is not necessary to be repaired because they are postomitotic cells and their nuclear genomes are never replicated. However, our results strongly suggest that the maintenance and precise transcription of nuclear genonme is essential for the functions and survival of brain and neuronal cells, and further the maintenance of mitochondrial DNA is important in order to supply the energy essential for their function.Since we have succeeded in establishing mutant mice for the three genes in this project, we are going to analyze the phenotypes of these mutant mice with combination of models for several neurodegenerative diseases. Our final goal is to establish biologcal roles of these defense mechanisms against oxidative DNA damage in brain and neuronal cells. Less

神经元前体细胞在哺乳动物发育的胚胎和出生后早期阶段增殖，然而，它们在分化为功能性神经元后失去增殖潜力，预计神经元在个体的整个生命中都能存活并发挥作用，然而，在衰老过程中积累的各种损伤似乎会影响神经元的功能。神经元功能（例如释放神经递质）所需的大部分能量是由线粒体中的氧化磷酸化提供的，其中活性氧（ROS）不断产生，因此，神经元面临危险。 ROS 的氧化损伤，作为维持神经元功能的结果。在这个项目中，基于 DNA 和核苷酸的氧化损伤对维持大脑和神经元细胞功能造成困扰的想法，我们描述了针对氧化 DNA 的防御机制对包括人类在内的哺乳动物造成的损害，即氧化核苷酸的净化和DNA中氧化碱基的修复。我们已经确定了参与该过程的三种酶，氧化嘌呤研究人员对MTH1基因编码的核苷三磷酸酶、MYH基因编码的2-羟基腺嘌呤(2-OH-A)/腺嘌呤DNA糖基化酶、OGG1基因编码的8-氧代鸟嘌呤(8-oxoG)DNA糖基化酶进行了分析，并分析了它们的功能和调控机制。我们证明这三种酶参与核和线粒体基因组的维持，并进一步获得了表明的数据。迄今为止，人们普遍认为大脑或神经元细胞中的DNA损伤不需要修复，因为它们是有丝分裂后细胞，其核基因组永远不会复制然而，我们的结果强烈表明，核基因组的维持和精确转录对于大脑和神经元细胞的功能和生存至关重要，并且线粒体 DNA 的维持对于提供其功能必需的能量也很重要。有在这个项目中成功建立了这三个基因的突变小鼠，我们将结合几种神经退行性疾病的模型来分析这些突变小鼠的表型，我们的最终目标是建立这些防御机制对抗氧化DNA损伤的生物学作用。大脑和神经细胞较少。

项目成果

期刊论文数量（148）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Miyako,K.,Takamatsu,C.,Umeda,S.,Tajiri,T.,Furuichi,M.,Nakabeppu,Y.,Sekiguchi,M.,Hamasaki,N.,Takeshige,K.,and Kang,D: "Accumulation of Adenine DNA Glycosylase-sensitive Sites in Human Mitochondrial DNA."J.Biol.Chem.. 275・16. 12326-12330 (2000)

Miyako, K.、Takamatsu, C.、Umeda, S.、Tajiri, T.、Furuichi, M.、Nakabeppu, Y.、Sekiguchi, M.、Hamasaki, N.、Takeshige, K. 和 Kang, D： “人类线粒体 DNA 中腺嘌呤 DNA 糖基化酶敏感位点的积累。”J.Biol.Chem. 275・16（2000）。