本文選題：亨廷頓病 + 亨廷頓蛋白�。� 參考：《生物化學(xué)與生物物理進(jìn)展》2017年09期

【摘要】：亨廷頓病(Huntington’s disease,HD)是一種常染色體顯性遺傳的神經(jīng)退行性疾病,是由于亨廷頓基因(Htt)發(fā)生突變而導(dǎo)致的,突變的亨廷頓蛋白(mutant huntingtin,m Htt)會(huì)在胞內(nèi)產(chǎn)生聚集引起細(xì)胞功能異常并引發(fā)神經(jīng)退行.亨廷頓病的具體分子機(jī)制有多種假說(shuō),例如氧化壓力、線粒體功能異常等.2017年《自然》(Nature)雜志發(fā)文認(rèn)為DNA損傷修復(fù)異常是神經(jīng)退行性疾病發(fā)生的共同機(jī)制.大量證據(jù)顯示,DNA損傷修復(fù)在HD的發(fā)生中扮演著重要角色,Htt突變會(huì)引發(fā)多種DNA損傷以及修復(fù)通路的過(guò)度激活,HD細(xì)胞對(duì)離子輻射敏感同時(shí)存在雙鏈斷裂修復(fù)缺陷,同時(shí)Htt突變會(huì)阻礙DNA修復(fù)關(guān)鍵因子共濟(jì)失調(diào)毛細(xì)血管擴(kuò)張突變(ATM)蛋白在DNA修復(fù)中正常功能的發(fā)揮.DNA修復(fù)通路還是HD發(fā)病年齡的重要影響因素.此外,將ATM做為治療靶點(diǎn)能夠減輕突變Htt引發(fā)的細(xì)胞毒性以及動(dòng)物模型的疾病進(jìn)程.ATM還在維持細(xì)胞穩(wěn)態(tài)和線粒體信號(hào)中起著關(guān)鍵作用,鑒于線粒體異常與HD發(fā)病的相關(guān)性,ATM作為治療靶點(diǎn)的分子機(jī)制也逐漸明朗.本文著重于介紹DNA損傷修復(fù)與亨廷頓病的發(fā)生機(jī)理的研究進(jìn)展,為闡明HD的發(fā)病機(jī)理,開(kāi)發(fā)有效的治療手段提供思路.
[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.
【作者單位】： 南開(kāi)大學(xué)經(jīng)濟(jì)與社會(huì)發(fā)展研究院與中國(guó)科學(xué)技術(shù)發(fā)展戰(zhàn)略研究院聯(lián)合博士后工作站;中國(guó)科學(xué)院動(dòng)物研究所膜生物學(xué)國(guó)家重點(diǎn)實(shí)驗(yàn)室;
【基金】：國(guó)家自然科學(xué)基金資助項(xiàng)目(30970931)~~
【分類號(hào)】：R742.2

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