Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-1079, USA.
J Alzheimers Dis. 2011;24 Suppl 2(0 2):183-98. doi: 10.3233/JAD-2011-110281.
The neurons in the central nervous system (CNS) with high O2 consumption and prolonged life span are chronically exposed to high levels of reactive oxygen species (ROS). Accumulation of ROS-induced genome damage in the form of oxidized bases and single-strand breaks (SSBs) as well as their defective or reduced repair in the brain has been implicated in the etiology of various neurological disorders including Alzheimer's/Parkinson's diseases (AD/PD). Although inactivating mutations in some DNA repair genes have been linked to hereditary neurodegenerative diseases, the underlying mechanisms of repair deficiencies for the sporadic diseases is not understood. The ROS-induced DNA damage is predominantly repaired via the highly conserved and regulated base excision/SSB repair (BER/SSBR) pathway. We recently made an interesting discovery that the transition metals iron and copper, which accumulate excessively in the brains of AD, PD, and other neurodegenerative diseases, act as a 'double-edged sword' by inducing genotoxic ROS and inhibiting DNA damage repair at the same time. These metals inhibit the base excision activity of NEIL family DNA glycosylases by oxidizing them, changing their structure, and inhibiting their binding to downstream repair proteins. Metal chelators and reducing agents partially reverse the inhibition, while curcumin with both chelating and reducing activities reverses the inhibition nearly completely. In this review, we have discussed the possible etiological linkage of BER/SSBR defects to neurodegenerative diseases and the therapeutic potential of metal chelators in restoring DNA repair capacity.
中枢神经系统 (CNS) 中的神经元耗氧量高，寿命长，因此会长期暴露于高水平的活性氧 (ROS) 中。ROS 诱导的氧化碱基和单链断裂 (SSB) 等基因组损伤在大脑中的积累，以及其缺陷或减少修复，与包括阿尔茨海默病/帕金森病 (AD/PD) 在内的各种神经退行性疾病的病因有关。尽管一些 DNA 修复基因的失活突变与遗传性神经退行性疾病有关，但散发性疾病的修复缺陷的潜在机制尚不清楚。ROS 诱导的 DNA 损伤主要通过高度保守和调节的碱基切除/SSB 修复 (BER/SSBR) 途径进行修复。我们最近有了一个有趣的发现，即铁和铜等过渡金属在 AD、PD 和其他神经退行性疾病的大脑中过度积累，它们通过诱导遗传毒性 ROS 并同时抑制 DNA 损伤修复，充当了一把“双刃剑”。这些金属通过氧化、改变其结构和抑制其与下游修复蛋白的结合，抑制 NEIL 家族 DNA 糖苷酶的碱基切除活性。金属螯合剂和还原剂部分逆转了抑制作用，而同时具有螯合和还原作用的姜黄素几乎完全逆转了抑制作用。在这篇综述中，我们讨论了 BER/SSBR 缺陷与神经退行性疾病之间可能的病因联系，以及金属螯合剂恢复 DNA 修复能力的治疗潜力。
