DNA repair deficiency in neurodegeneration.
DNA repair deficiency in neurodegeneration.
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DOI：
10.1016/j.pneurobio.2011.04.013
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发表时间：
2011-07
影响因子：
6.7
通讯作者：
Stevnsner, Tinna
中科院分区：
文献类型：
--
作者：
Jeppesen, Dennis Kjolhede;Bohr, Vilhelm A.;Stevnsner, Tinna
关键词：
细胞核和线粒体DNA损伤修复缺陷与几种神经退行性疾病有关。最近的许多实验结果表明，有丝分裂后的神经元特别容易积累未修复的DNA损伤，可能导致进行性神经退行性变。核苷酸切除修复是负责去除螺旋扭曲DNA损伤的细胞途径，在许多具有神经退行性表型的疾病中发现这种修复缺陷，包括色素干皮病和Cockayne综合征。修复氧化性碱基损伤的主要途径是碱基切除修复，鉴于神经元的高氧代谢率，这种修复对神经元至关重要。错配修复纠正了复制过程中产生的碱基错配，有证据表明DNA氧化损伤可导致该途径扩大三核苷酸重复，从而导致亨廷顿氏病。单链断裂是一种常见的DNA损伤，与神经退行性疾病、共济失调-动眼性失用症-1和脊髓小脑性共济失调伴轴索神经性病变-1有关。DNA双链断裂是一种毒性损伤，其修复主要有同源重组和非同源末端连接两种途径。共济失调毛细血管扩张和相关疾病与缺陷的这些途径表明，这种缺陷可导致早期儿童神经变性。衰老是神经退行性疾病的危险因素，线粒体DNA氧化损伤的积累可能与年龄相关的神经退行性疾病阿尔茨海默病、帕金森病和肌萎缩性侧索硬化症有关。WRN蛋白的突变会导致早老性疾病维尔纳综合征，这是一种以神经变性为特征的疾病。在这篇文章中，我们回顾了DNA修复通路缺陷与神经退行性变的证据。
Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington’s disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.
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