Evidence that OGG1 glycosylase protects neurons against oxidative DNA damage and cell death under ischemic conditions

Dong Liu, Deborah L. Croteau, Nadja Souza-Pinto, Michael Pitta, Jingyan Tian, Christopher Wu, Haiyang Jiang, Khadija Mustafa, Guido Keijzers, Vilhelm A. Bohr, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

7,8-Dihydro-8-oxoguanine DNA glycosylase (OGG1) is a major DNA glycosylase involved in base-excision repair (BER) of oxidative DNA damage to nuclear and mitochondrial DNA (mtDNA). We used OGG1-deficient (OGG1-/-) mice to examine the possible roles of OGG1 in the vulnerability of neurons to ischemic and oxidative stress. After exposure of cultured neurons to oxidative and metabolic stress levels of OGG1 in the nucleus were elevated and mitochondria exhibited fragmentation and increased levels of the mitochondrial fission protein dynamin-related protein 1 (Drp1) and reduced membrane potential. Cortical neurons isolated from OGG1-/-mice were more vulnerable to oxidative insults than were OGG1-/-neurons, and OGG1 -/-mice developed larger cortical infarcts and behavioral deficits after permanent middle cerebral artery occlusion compared with OGG1 -/-mice. Accumulations of oxidative DNA base lesions (8-oxoG, FapyAde, and FapyGua) were elevated in response to ischemia in both the ipsilateral and contralateral hemispheres, and to a greater extent in the contralateral cortex of OGG1-/-mice compared with OGG1 -/-mice. Ischemia-induced elevation of 8-oxoG incision activity involved increased levels of a nuclear isoform OGG1, suggesting an adaptive response to oxidative nuclear DNA damage. Thus, OGG1 has a pivotal role in repairing oxidative damage to nuclear DNA under ischemic conditions, thereby reducing brain damage and improving functional outcome.

Original languageEnglish (US)
Pages (from-to)680-692
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume31
Issue number2
DOIs
StatePublished - Feb 2011
Externally publishedYes

Keywords

  • 8-oxoG
  • BER
  • DNA repair
  • Drp1
  • focal ischemic stroke
  • mitochondria
  • OGG1
  • XRCC1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Neurology

Fingerprint Dive into the research topics of 'Evidence that OGG1 glycosylase protects neurons against oxidative DNA damage and cell death under ischemic conditions'. Together they form a unique fingerprint.

  • Cite this

    Liu, D., Croteau, D. L., Souza-Pinto, N., Pitta, M., Tian, J., Wu, C., Jiang, H., Mustafa, K., Keijzers, G., Bohr, V. A., & Mattson, M. P. (2011). Evidence that OGG1 glycosylase protects neurons against oxidative DNA damage and cell death under ischemic conditions. Journal of Cerebral Blood Flow and Metabolism, 31(2), 680-692. https://doi.org/10.1038/jcbfm.2010.147