＜Symposium III＞Oxidative damage in brain genome and neuroprotection
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概要
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Oxidative DNA lesions, such as 8-oxoguanine（ 8-oxoG）, accumulate in nuclear and mitochondrial genomesduring 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 withthree distinct enzymes, MTH1, OGG1 and MUTYH. MTH1 hydrolyzes oxidized purine nucleoside triphosphates, suchas 8-oxo-dGTP to their monophosphate forms. OGG1 and MUTYH are DNA glycosylases excising 8-oxoG oppositecytosine and adenine opposite 8-oxoG in DNA, respectively. We showed a signifi cant increase in 8-oxoG in cellularDNA as well as altered expression of MTH1, OGG1 and MUTYH in PD and AD brains, suggesting that the buildup of8-oxoG may cause neurodegeneration. We have shown that buildup of 8-oxoG in either nuclear or mitochondrial DNAcauses MUTYH-dependent cell death through two distinct pathways, and that accumulation of oxidized nucleotidesin nucleotide pools also causes MUTYH-dependent cell death. MTH1-null mice exhibited an increased buildup of8-oxoG in striatal mitochondrial DNA followed by more extreme neuronal dysfunction after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration, while hMTH1-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 doubleknockout（DKO） mice lacking OGG1 and MTH1, and to a lesser extent OGG1-KO mice, are signifi cantly sensitive to3-NP-induced striatal degeneration, in comparison to MTH1-KO or wild-type mice, while MUTYH defi ciency increasesresistance to 3-NP in OGG1-KO or wild-type background. We thus demonstrated that 8-oxoG accumulated in braingenomes causes neurodegeneration in a MUTYH-dependent manner, and which is effi ciently suppressed by MTH1and OGG1.
著者
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Nakabeppu Yusaku
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institut
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Sheng Zijing
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institut
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Oka Sugako
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institut
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Nakabeppu Yusaku
Division Of Neurofunctional Genomics Department Of Immunobiology And Neuroscience Medical Institute
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Oka Sugako
Division Of Neurofunctional Genomics Department Of Immunobiology And Neuroscience Medical Institute
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Sheng Zijing
Division Of Neuroanatomy Department Of Neuroscience Yamaguchi University School Of Medicine
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Sheng Zijing
Division Of Neurofunctional Genomics Department Of Immunobiology And Neuroscience Medical Institute
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Nakabeppu Yusaku
Division Of Neurofunctional Genomics Department Of Immunobiology And Neuroscience Medical Institute
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