Mayo Clinic的研究人員和美國健康研究院以及挪威奧斯陸大學(xué)的研究人員合作發(fā)現(xiàn),，身體基因修復(fù)系統(tǒng)的一個(gè)錯(cuò)誤可以導(dǎo)致亨廷頓癥的發(fā)生,。
亨廷頓舞蹈病(Huntington's disease,HD)是一種由IT15基因上CAG重復(fù)序列異常擴(kuò)展所致常染色體顯性遺傳的神經(jīng)退行性疾病。到目前為止,，人們還不清楚這種疾病如何開始,，只是知道它無法治愈。這項(xiàng)新發(fā)現(xiàn)發(fā)表在《自然》雜志的網(wǎng)絡(luò)版上,。
研究人員發(fā)現(xiàn),，當(dāng)因氧化損傷引發(fā)的DNA中單鏈斷裂被修復(fù)時(shí)，亨廷頓基因會(huì)連續(xù)添加多于的替代片段,。經(jīng)過一段時(shí)間,，這種擴(kuò)充（尤其在神經(jīng)細(xì)胞中）產(chǎn)生了有害作用。
這些發(fā)現(xiàn)之所以具有重要意義是因?yàn)?，人們目前?duì)亨廷頓癥還知之甚少,。這項(xiàng)發(fā)現(xiàn)首次證實(shí)了DNA修復(fù)和這種疾病發(fā)生之間的聯(lián)系。
研究中所使用的小鼠模型攜帶了人類亨廷頓基因,。研究人員指出,，這種大量重復(fù)的替代修復(fù)片段似乎到這些轉(zhuǎn)基因小鼠4個(gè)月大時(shí)趨于穩(wěn)定。在這個(gè)時(shí)間點(diǎn)之后,，片段擴(kuò)張并繼續(xù)隨著年齡的增加而增加。研究人員還證實(shí)這種片段的大量擴(kuò)增還導(dǎo)致細(xì)胞毒性,，使細(xì)胞不能增殖,。
在進(jìn)一步的研究中，研究組刪除了一種與DNA修復(fù)有關(guān)的關(guān)鍵酶OGG1,，并發(fā)現(xiàn)這種操作能終止或減少片段的增加,。這個(gè)發(fā)現(xiàn)揭示出，OGG1可能作為干擾這種疾病發(fā)生的一個(gè)治療性靶標(biāo)候選,。
原始出處:
Nature advance online publication 22 April 2007 | doi:10.1038/nature05778; Received 31 August 2006; Accepted 2 April 2007; Published online 22 April 2007
OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells
Irina V. Kovtun1, Yuan Liu5, Magnar Bjoras4, Arne Klungland4, Samuel H. Wilson5 & Cynthia T. McMurray1,2,3
Department of Pharmacology and Experimental Therapeutics,
Department of Biochemistry and Molecular Biology,
Neuroscience Program Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA
Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet-Radiumhospitalet HF, University of Oslo, N-0027 Oslo, Norway
Laboratory of Structural Biology, National Institute of Environmental Health Sciences/National Institutes of Health, 111 TW Alexander Drive, Research Triangle Park, North Carolina 27709, USA
Correspondence to: Cynthia T. McMurray1,2,3 Correspondence and requests for materials should be addressed to C.T.M. (Email: [email protected]).
Top of page
Abstract
Although oxidative damage has long been associated with ageing and neurological disease, mechanistic connections of oxidation to these phenotypes have remained elusive. Here we show that the age-dependent somatic mutation associated with Huntington's disease occurs in the process of removing oxidized base lesions, and is remarkably dependent on a single base excision repair enzyme, 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1). Both in vivo and in vitro results support a 'toxic oxidation' model in which OGG1 initiates an escalating oxidation–excision cycle that leads to progressive age-dependent expansion. Age-dependent CAG expansion provides a direct molecular link between oxidative damage and toxicity in post-mitotic neurons through a DNA damage response, and error-prone repair of single-strand breaks.
