＜Symposium III＞Oxidative damage in brain genome and neuroprotection

フォーマット:

論文

責任表示:

Nakabeppu, Yusaku ; Sheng, Zijing ; Oka, Sugako

言語:

英語

出版情報:

弘前大学大学院医学研究科・弘前医学会, 2010-07-08

著者名:

• Nakabeppu, Yusaku
• Sheng, Zijing
• Oka, Sugako

掲載情報:

弘前医学

ISSN:

0439-1721      

巻:

61

通号:

Supplement

開始ページ:

S70

終了ページ:

S79

バージョン:

publisher

概要:

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&rs … quo;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 signifi cant 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. MTH1-null mice exhibited an increased buildup of 8-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 to 3-NP-induced striatal degeneration, in comparison to MTH1-KO or wild-type mice, while MUTYH defi ciency 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 effi ciently suppressed by MTH1 and OGG1. 続きを見る

URL:

http://hdl.handle.net/10129/3672