氧化損傷幾十年來一直被與衰老和神經(jīng)退化疾病聯(lián)系在一起，但氧化與衰老之間的生理聯(lián)系卻仍然不很清楚?，F(xiàn)在,，這種聯(lián)系可能已經(jīng)被找到了,。亨廷頓病和其他幾種神經(jīng)退化疾病涉及以3個核苷酸為一組的CAG重復(fù)序列的擴張,。在人類亨廷頓病的小鼠模型中，這種擴張在生命中期出現(xiàn),，并且在整個生命過程中繼續(xù),。這種擴張發(fā)生在終端分異的細胞中，與氧化損傷有關(guān),。Glycolase OGG1中所存在的缺陷衰減依賴于年齡的重復(fù)擴張,，而且因為OGG1是一種DNA修復(fù)酶，所以似乎氧化損傷的畸形修復(fù)誘發(fā)了這種疾病,。這項工作為停止或減緩這種疾病發(fā)病的藥物找到了可能的作用目標(biāo),。
英文原文：
Article
Nature 447, 447-452 (24 May 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]).
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.
