DNA损伤修复与亨廷顿病的发生机制

发布时间：2018-04-14 18:13

本文选题：亨廷顿病 + 亨廷顿蛋白　；参考：《生物化学与生物物理进展》2017年09期

【摘要】：亨廷顿病(Huntington’s disease,HD)是一种常染色体显性遗传的神经退行性疾病,是由于亨廷顿基因(Htt)发生突变而导致的,突变的亨廷顿蛋白(mutant huntingtin,m Htt)会在胞内产生聚集引起细胞功能异常并引发神经退行.亨廷顿病的具体分子机制有多种假说,例如氧化压力、线粒体功能异常等.2017年《自然》(Nature)杂志发文认为DNA损伤修复异常是神经退行性疾病发生的共同机制.大量证据显示,DNA损伤修复在HD的发生中扮演着重要角色,Htt突变会引发多种DNA损伤以及修复通路的过度激活,HD细胞对离子辐射敏感同时存在双链断裂修复缺陷,同时Htt突变会阻碍DNA修复关键因子共济失调毛细血管扩张突变(ATM)蛋白在DNA修复中正常功能的发挥.DNA修复通路还是HD发病年龄的重要影响因素.此外,将ATM做为治疗靶点能够减轻突变Htt引发的细胞毒性以及动物模型的疾病进程.ATM还在维持细胞稳态和线粒体信号中起着关键作用,鉴于线粒体异常与HD发病的相关性,ATM作为治疗靶点的分子机制也逐渐明朗.本文着重于介绍DNA损伤修复与亨廷顿病的发生机理的研究进展,为阐明HD的发病机理,开发有效的治疗手段提供思路.
[Abstract]:Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by mutations in the Huntington gene.Mutated Huntington protein can produce aggregation in the cell and induce abnormal cell function and neurodegeneracy.There are many hypotheses about the specific molecular mechanism of Huntington's disease, such as oxidative stress, abnormal function of mitochondria, etc. The 2017 journal Nature argues that abnormal repair of DNA damage is the common mechanism of neurodegenerative diseases.A large number of evidences have shown that DNA damage repair plays an important role in the pathogenesis of HD. Htt mutation may lead to multiple DNA damage and excessive activation of repair pathway. HD cells are also sensitive to ionizing radiation and have double-strand break repair defects.At the same time, the mutation of Htt will hinder the DNA repair key factor, ataxia, telangiectasia mutation and ATM) protein in DNA repair, the normal function of the DNA repair pathway, or an important factor affecting the onset age of HD.In addition, using ATM as a therapeutic target can reduce the cytotoxicity induced by mutant Htt and the disease progression in animal models. ATM also plays a key role in maintaining cellular homeostasis and mitochondrial signaling.In view of the correlation between mitochondrial abnormalities and HD pathogenesis, the molecular mechanism of ATM as a therapeutic target is becoming clear.This paper focuses on the research progress of DNA damage repair and Huntington's disease in order to elucidate the pathogenesis of HD and to develop effective treatment methods.
【作者单位】：南开大学经济与社会发展研究院与中国科学技术发展战略研究院联合博士后工作站;中国科学院动物研究所膜生物学国家重点实验室;
【基金】：国家自然科学基金资助项目(30970931)~~
【分类号】：R742.2

【相似文献】