Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?
Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?
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DOI：
10.1016/j.mad.2016.09.005
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发表时间：
2017-01
影响因子：
5.3
通讯作者：
Hegde ML
中科院分区：
文献类型：
--
作者：
Wang H;Dharmalingam P;Vasquez V;Mitra J;Boldogh I;Rao KS;Kent TA;Mitra S;Hegde ML
神经元是含氧量最高的细胞之一，对它们来说，最重要的挑战是长期暴露于内源性活性氧物种(ROS)造成的基因组损害，ROS是细胞呼吸副产物。在这些长期存活的有丝分裂后细胞中，与高转录水平相关的强烈代谢活动使它们容易受到氧化基因组损伤，包括DNA链断裂和突变碱基损伤。越来越多的证据表明，在加速老化和进行性神经变性过程中，中枢神经系统(CNS)中积累了未修复的DNA损伤。DNA修复或DNA损伤反应(DDR)信号基因的几个胚系突变独特地表现在神经元功能障碍的表型中，并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，促氧化金属、ROS和错误折叠的淀粉样蛋白不仅导致中枢神经系统基因组损伤，而且阻碍它们的修复/DDR信号导致持续损伤积累，这是散发性神经变性的共同特征。本文就DNA损伤与修复失衡的病因学意义、DDR信号异常引发神经退行性变以及DDR作为改善神经退行性疾病的靶点等方面的最新进展作一综述。
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 ageing 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.