DNA损伤修复与亨廷顿病的发生机制  

DNA Damage Response and The Pathogenesis of Huntington's Disease

作　　者：朱姝 唐铁山[2] 

机构地区：[1]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,北京100038 [2]中国科学院动物研究所膜生物学国家重点实验室,北京100101

出　　处：《生物化学与生物物理进展》2017年第9期727-736,共10页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金资助项目(30970931)~~

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.Huntington＇s disease（HD） is an autosomal dominant hereditary neurodegenerative disorder, caused by mutation of Htt gene which encoding huntingtin（Htt）. Expanded Htt proteins form aggregates accumulated in cells and result in progressive neuronal degeneration and dysfunction. There are many hypothesis on the pathogenesis of HD, such as oxidative stress and mitochondrial dysfunction. Report on Nature in 2017 highlights that DNA repair as a shared mechanism in neurodegenerative disorders. More and more evidences indicate that DNA repair mechanisms have been implicated in Huntington＇s Disease, mutant Htt triggers different types of DNA lesions and excessive activation of DNA damage response. HD is associated with cellular radiosensitivity and double strand break repair defect, and mutant Htt impact the normal function of ATM（ataxia tetangtectasia mutated） in DNA repair. Moreover, DNA repair proteins also impact the onset age of HD. Targeting ATM can ameliorates mutant Huntingtin toxicity in cells and animal models of HD. ATM has a important role in regulating celluar homeostasis and mitochondria signaling, so the mechanism of targeting ATM is more and more clear. This review introduces recent advances in HD and DNA damage response, opens a new direction for study of pathogenic mechanism and development of therapies.

关 键 词：亨廷顿病 亨廷顿蛋白 DNA损伤修复 ATM 发病年龄 

分 类 号：Q189[生物学—神经生物学] Q291[生物学—普通生物学]