Molecular mechanisms of neuropathogenesis associated with the defects of DNA repair system

DNA修复系统缺陷相关神经发病的分子机制

基本信息

批准号：
18500292
负责人：
ENOKIDO Yasushi
金额：
$ 2.57万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Recent studies have shown that the defect of DNA repair/damage response mechanism in the nervous system closely associate with pathology underlying various neurodegenerative diseases. Accumulating results suggest that DNA damage may reduce transcriptional expression of genes involved in learning, memory and neuronal survival to initiate a program of brain ageing and pathogenesis. In this study, we focused on the molecular basis of DNA repair and damage responses underlying neurodegenerative diseases.We performed a proteome analysis of soluble nuclear proteins prepared from neurons expressing mutant huntingtin exon 1 fragment protein which contains abnormally expanded poly-glutamine repeat (mHtt), and found that mHtt reduces the concentration of nuclear HMGB1 protein level. We also found that the reduction of nuclear HMGB1 causes DNA double-strand break (DDSB)-mediated neuronal damage in Huntinton's disease pathology. Using gene transgenic animals of mouse and fly that overexpressing DNA repair/damage response genes, we found that the improvement of DNA repair significantly recovers the symptoms of Huntinton's disease pathology. Furthermore, we investigated the regional and cell-type specific changes of HMGB1 and DDSB accumulation during the aging of mouse brain. HMGB1 is localized in the nuclei of neurons and astrocytes, and the protein level changes in various brain regions age-dependently. HMGB1 reduces in neurons, whereas it increases in astrocytes during aging. In contrast, DDSB remarkably accumulates in neurons, but it does not change significantly in astrocytes during aging. These results indicate that HMGB1 expression is differentially regulated between neuron and astrocyte, and suggest that the reduction of nuclear HMGB1 might be associated with DDSB-mediated neuronal dysfunction in the aging brain.Our findings might provide us an effective strategy for developing new therapeutics against various neurodegenerative disorders.

最近的研究表明，神经系统中DNA修复/损伤反应机制的缺陷与各种神经退行性疾病的病理密切相关。积累的结果表明，DNA损伤可以减少与学习，记忆和神经元存活有关的基因的转录表达，以启动大脑衰老和发病机理程序。在这项研究中，我们集中于DNA修复的分子基础和神经退行性疾病的损伤反应。我们对来自表达突变体外显蛋1片段1片段的神经元制备的可溶性核蛋白进行了蛋白质组分析，该神经元含有异常膨胀的多葡萄糖重复（MHTT），并发现了MHT的浓缩水平。我们还发现，核HMGB1的减少会导致DNA双链断裂（DDSB）介导的亨特顿病病理学的神经元损伤。使用小鼠的基因转基因动物并飞行过表达DNA修复/损伤反应基因，我们发现DNA修复的改善可显着恢复Huntinton疾病病理学的症状。此外，我们研究了小鼠脑老化期间HMGB1和DDSB积累的区域和细胞类型的特异性变化。 HMGB1位于神经元和星形胶质细胞的细胞核中，蛋白质水平在各个大脑区域的变化依赖性。 HMGB1在神经元中降低，而衰老过程中星形胶质细胞的增加。相比之下，DDSB在神经元中积累了明显的积累，但在衰老过程中，星形胶质细胞的变化并未发生显着变化。这些结果表明，HMGB1表达在神经元和星形胶质细胞之间受到差异调节，并表明核HMGB1的减少可能与DDSB介导的衰老大脑中的DDSB介导的神经元功能障碍有关。