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

神经元前体细胞在哺乳动物胚胎和出生后早期发育阶段增殖，但在分化为功能性神经元后失去增殖能力。神经元在个体的整个生命过程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导致了它们的退化。神经元功能所需的大部分能量，如神经递质的释放，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。本研究基于DNA和核苷酸的氧化损伤对脑和神经细胞功能的维持是有害的这一观点，对包括人类在内的哺乳动物抗氧化DNA损伤的防御机制进行了研究，即氧化核苷酸的消毒和氧化修饰， 关于我们 本研究鉴定了MTH 1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OGG 1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。我们证明了这三种酶都参与了核基因组和线粒体基因组的维持，并进一步获得了它们表达的改变与人类神经再生性疾病的过程有关的数据，迄今为止，人们已经接受脑或神经细胞中DNA损伤不需要修复，因为它们是有丝分裂后的细胞，它们的核基因组从不复制。然而，我们的研究结果强烈表明，核基因组的维持和精确转录对脑和神经细胞的功能和存活至关重要，而且线粒体DNA的维持也很重要，以便为其功能提供必要的能量。由于我们在本项目中成功地建立了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。我们的最终目标是确定这些防御机制在脑和神经细胞中对氧化DNA损伤的生物学作用。少

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