Oxidative damage in brain genome and neuroprotection

Yusaku Nakabeppu, Zijing Sheng, Sugako Oka

Research output: Contribution to journalConference article

Abstract

Oxidative DNA lesions, such as 8-oxoguanine (8-oxoG), accumulate in nuclear and mitochondrial genomes during aging, and such accumulation is known to dramatically increase in patient brains with Parkinson's disease (PD) or Alzheimer's disease (AD). To counteract oxidative damage to nucleic acids, human and rodents are equipped with three distinct enzymes, MTH1, OGG1 and MUTYH. MTH1 hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP to their monophosphate forms. OGG1 and MUTYH are DNA glycosylases excising 8-oxoG opposite cytosine and adenine opposite 8-oxoG in DNA, respectively. We showed a significant increase in 8-oxoG in cellular DNA as well as altered expression of MTH1, OGG1 and MUTYH in PD and AD brains, suggesting that the buildup of 8-oxoG may cause neurodegeneration. We have shown that buildup of 8-oxoG in either nuclear or mitochondrial DNA causes MUTYH-dependent cell death through two distinct pathways, and that accumulation of oxidized nucleotides in nucleotide pools also causes MUTYH-dependent cell death. MTHl-null mice exhibited an increased buildup of 8-oxoG in striatal mitochondrial DNA followed by more extreme neuronal dysfunction after l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration, while hMTHl-transgenic mice are resistant to a mitochondrial neurotoxin, 3-nitropropionic acid (3-NP)-induced striatal degeneration, in comparison to wild-type mice. We found that double-knockout (DKO) mice lacking OGG1 and MTH1, and to a lesser extent OGG1-KO mice, are significantly sensitive to 3-NP-induced striatal degeneration, in comparison to MTH1-KO or wild-type mice, while MUTYH deficiency increases resistance to 3-NP in OGG1-KO or wild-type background. We thus demonstrated that 8-oxoG accumulated in brain genomes causes neurodegeneration in a MUTYH-dependent manner, and which is efficiently suppressed by MTH1 and OGG1.

Original languageEnglish
Pages (from-to)S70-S79
JournalHirosaki Medical Journal
Volume61
Issue numberSUPPL.
Publication statusPublished - Jul 8 2010

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All Science Journal Classification (ASJC) codes

  • Medicine(all)

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