氧化损伤几十年来一直被与衰老和神经退化疾病联系在一起，但氧化与衰老之间的生理联系却仍然不很清楚。现在，这种联系可能已经被找到了。亨廷顿病和其他几种神经退化疾病涉及以3个核苷酸为一组的CAG重复序列的扩张。在人类亨廷顿病的小鼠模型中，这种扩张在生命中期出现，并且在整个生命过程中继续。这种扩张发生在终端分异的细胞中，与氧化损伤有关。Glycolase OGG1中所存在的缺陷衰减依赖于年龄的重复扩张，而且因为OGG1是一种DNA修复酶，所以似乎氧化损伤的畸形修复诱发了这种疾病。这项工作为停止或减缓这种疾病发病的药物找到了可能的作用目标。
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: mcmurray.cynthia@mayo.edu).
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.
