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早期产后阶段增殖，但是它们在分化为功能性神经元后失去了增殖潜力。预计神经元将在一个人的整个生命中生存并起作用，但是，在衰老期间加速的Variotus损害似乎会导致其退化。神经递质所需的大多数能量是通过线粒体中的氧化磷酸化提供的，其中活性氧（ROS）是连续产生的。 That, neurons are exposed to danger of oxide damage by ROS, as a consequence of maintenance of their neuronal function.In this project, based on the idea that oxide damage of DNA and nucleartoides are detrimental for maintaining functions of brain and neuronal cells, we have characterised the defense mechanisms against oxide DNA damage in mammals including humanbeing, that is, sanitization of Oxidized nuclearotides and … More repair of oxidized bases in DNA.We have identified three enzymes involved in the processes, oxidized pure nuclear lateral triphosphatase encoded by MTH1 gene, 2-hydroxydenine (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其表达的调节机制。我们证明了三种酶参与维持核和线粒体基因组，并获得了进一步的数据，表明其表达的变化与人类中神经性疾病的过程有关。 However, our results strongly suggest that the Maintenance and precision 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神经退行性疾病。我们的最终目标是建立针对脑和神经元细胞中氧化物DNA损伤的这些防御机制的生物智能作用。较少的

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）。