A foremost challenge for the neurons, which are among the most oxygenated cells, is the genome damage caused by chronic exposure to endogenous reactive oxygen species (ROS), formed as cellular respiratory byproducts. Strong metabolic activity associated with high transcriptional levels in these long lived post-mitotic cells render them vulnerable to oxidative genome damage, including DNA strand breaks and mutagenic base lesions. There is growing evidence for the accumulation of unrepaired DNA lesions in the central nervous system (CNS) during accelerated aging and progressive neurodegeneration. Several germ line mutations in DNA repair or DNA damage response (DDR) signaling genes are uniquely manifested in the phenotype of neuronal dysfunction and are etiologically linked to many neurodegenerative disorders. Studies in our lab and elsewhere revealed that pro-oxidant metals, ROS and misfolded amyloidogenic proteins not only contribute to genome damage in CNS, but also impede their repair/DDR signaling leading to persistent damage accumulation, a common feature in sporadic neurodegeneration. Here, we have reviewed recent advances in our understanding of the etiological implications of DNA damage vs. repair imbalance, abnormal DDR signaling in triggering neurodegeneration and potential of DDR as a target for the amelioration of neurodegenerative diseases.

中文翻译：

---

慢性氧化损伤以及神经元中的基因组修复缺陷是神经退行性的双重打击：损伤反应是潜在的治疗靶点吗？

对于神经元而言，这是氧合程度最高的细胞之一，面临的最主要挑战是长期暴露于作为细胞呼吸副产物形成的内源性活性氧（ROS）引起的基因组损伤。在这些长寿命的有丝分裂后细胞中，与高转录水平相关的强代谢活性使其易受氧化基因组损害，包括DNA链断裂和诱变性基础病变。越来越多的证据表明，在加速衰老和进行性神经退行性变期间，未修复的DNA损伤会在中枢神经系统（CNS）中积累。DNA修复或DNA损伤反应（DDR）信号基因中的几种种系突变独特地表现在神经元功能障碍的表型中，并且在病因上与许多神经退行性疾病有关。我们实验室和其他地方的研究表明，前氧化剂金属，ROS和折叠错误的淀粉样蛋白不仅会导致中枢神经系统的基因组损伤，还会阻碍其修复/ DDR信号传导，导致持续的损伤累积，这是散发性神经退行性变的常见特征。在这里，我们回顾了我们对DNA损伤与修复失衡的病因学涵义，在触发神经退行性病变中异常DDR信号转导以及将DDR作为缓解神经退行性疾病的靶标的潜力的认识上的最新进展。