Roles of the defense mechanisms against oxidative damage in nucleic acids for maintenance of brain cells

首席研究员Nakabeppu博士已经表明，活性氧对碱基或核苷酸的氧化或脱氨基作用通过这种异常碱基或核苷酸在细胞内的积累而导致细胞功能障碍。在这个项目中，我们探讨了氧化应激下引起神经元细胞死亡或神经元功能障碍的分子途径，通过检查Mth 1-，Ogg 1-，Mutyh-和Itpa -null小鼠和来自这些突变小鼠的细胞系，与野生型小鼠和细胞系进行比较。此外，还对AP-1转录因子fosB基因编码亚基及其下游靶基因galectin-1进行了功能分析，以探讨氧化应激对海马齿状回神经发生的调控机制，以及脑组织对氧化应激的反应。两年来，我们取得了以下成果。[1]我们已经证明，核酸的氧化是多巴胺神经元的神经功能障碍的原因之一，使用帕金森病模型小鼠。[2]我们发现，在线粒体毒素，3-硝基丙酸引起的纹状体中的棘状神经元的变性中，核酸的氧化损伤起着重要的作用。[3]我们阐明了细胞核或线粒体基因组中氧化碱基积累引起细胞死亡的分子途径。[4]阐明了线粒体核苷酸库氧化导致细胞死亡的分子途径及其防御机制。[5]探讨了氧化脱氨基嘌呤核苷三磷酸的杀菌机理。[6]我们的研究表明，fosB基因参与了氧化应激下海马齿状回神经发生的调节。[7]我们证明了半乳糖凝集素-1促进海马齿状回的神经发生。

The head investigator, Dr. Nakabeppu had shown that oxidation or deamination of bases or nucleotides by reactive oxygen species causes cellular dysfunction through accumulation of such aberrant bases or nucleotides within cells. In this project, we explored molecular pathways causing neuronal cell death or neuronal dysfunction under oxidative stress, by examining Mth1-, Ogg1-, Mutyh,- and Itpa -null mice and cell lines derived from these mutant mice, in comparison to wild-type mice and cell lines. Furthermore, functional analyses of fosB gene coding subunits of AP-1 transcription factor and its downstream target, galectin-1 were performed, in order to explore the regulatory mechanisms for the neurogenesis in hippocampal dentate gyrus under oxidative stress, as well as for the response to oxidative stress in brain. We have achieved the following results for 2 years.[1] We have demonstrated that oxidation of nucleic acids is one of causes for the neuronal dysfunction of dopamine neurons, using a model mice for Parkinsonism.[2] We showed that oxidative damage in nucleic acids plays a major role for degeneration of medium spiny neurons in the striatum caused by mitochondrial toxin, 3-nitropropionic acid.[3] We elucidated the molecular pathways for cell death caused by accumulation of oxidized bases in either nuclear or mitochondrial genomes.[4] We elucidated the molecular pathway for cell death caused by oxidation of mitochondrial nucleotide pool and the defense mechanism against it.[5] We explored the sanitizing mechanism for deaminated purine nucleoside triphosphates generated by oxidative deamination.[6] We have shown that fosB gene is involved in the regulation of neurogenesis in the hippocampal dentate gyrus under oxidative stress.[7] We demonstrated that galectin-1 promotes neurogenesis in the hippocampal dentate gyrus.