1. Department of Pharmacology and Experimental Therapeutics,
2. Department of Biochemistry and Molecular Biology,
3. Neuroscience Program Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA
4. Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, Rikshospitalet-Radiumhospitalet HF, University of Oslo, N-0027 Oslo, Norway
5. 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. McMurray^1,2,3 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.

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