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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产后早期阶段增殖，但在分化为功能神经元后它们失去增殖潜力。神经元预计会在个体的一生中存活并发挥作用，然而，衰老过程中积累的各种损伤似乎会导致神经元退化。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，线粒体中不断产生活性氧（ROS）。因此，由于神经元功能的维持，神经元面临着ROS氧化损伤的危险。在这个项目中，基于DNA和核苷酸的氧化损伤不利于维持大脑和神经元细胞功能的想法，我们描述了包括人类在内的哺乳动物针对氧化DNA损伤的防御机制，即氧化核苷酸的净化和……更多 DNA中的氧化碱基。我们鉴定了参与该过程的三种酶，MTH1基因编码的氧化嘌呤核苷三磷酸酶、MYH基因编码的2-羟基腺嘌呤（2-OH-A）/腺嘌呤DNA糖基化酶和OGG1基因编码的8-氧代鸟嘌呤（8-oxoG）DNA糖基化酶，并分析了它们的功能和表达调控机制。我们证明这三种酶参与核基因组和线粒体基因组的维持，并进一步获得的数据表明它们表达的改变参与了人类神经再生疾病的过程。到目前为止，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。由于我们在这个项目中成功建立了这三个基因的突变小鼠，我们将结合多种模型来分析这些突变小鼠的表型。神经退行性疾病。我们的最终目标是确定这些防御机制在大脑和神经元细胞中对抗 DNA 氧化损伤的生物学作用。较少的