8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair

Zijing Sheng, Sugako Oka, Daisuke Tsuchimoto, Nona Abolhassani, Hiroko Nomaru, Sakumi Kunihiko, Hidetaka Yamada, Yusaku Nakabeppu

Research output: Contribution to journalArticle

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Abstract

8-Oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species, is associated with carcinogenesis and neurodegeneration. Although the mechanism by which 8-oxoG causes carcinogenesis is well understood, the mechanism by which it causes neurodegeneration is unknown. Here, we report that neurodegeneration is triggered by MUTYH-mediated excision repair of 8-oxoG-paired adenine. Mutant mice lacking 8-oxo-2′-deoxyguanosine triphosphate-depleting (8-oxo-dGTP-depleting) MTH1 and/or 8-oxoG-excising OGG1 exhibited severe striatal neurodegeneration, whereas mutant mice lacking MUTYH or OGG1/MUTYH were resistant to neurodegeneration under conditions of oxidative stress. These results indicate that OGG1 and MTH1 are protective, while MUTYH promotes neurodegeneration. We observed that 8-oxoG accumulated in the mitochondrial DNA of neurons and caused calpain-dependent neuronal loss, while delayed nuclear accumulation of 8-oxoG in microglia resulted in PARP-dependent activation of apoptosis-inducing factor and exacerbated microgliosis. These results revealed that neurodegeneration is a complex process caused by 8-oxoG accumulation in the genomes of neurons and microglia. Different signaling pathways were triggered by the accumulation of single-strand breaks in each type of DNA generated during base excision repair initiated by MUTYH, suggesting that suppression of MUTYH may protect the brain under conditions of oxidative stress.

Original languageEnglish
Pages (from-to)4344-4361
Number of pages18
JournalJournal of Clinical Investigation
Volume122
Issue number12
DOIs
Publication statusPublished - Dec 3 2012

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Microglia
DNA Repair
Carcinogenesis
Oxidative Stress
Apoptosis Inducing Factor
Neurons
Corpus Striatum
Calpain
DNA
Adenine
Mitochondrial DNA
Reactive Oxygen Species
Genome
Brain
8-hydroxyguanine
8-oxodeoxyguanosine triphosphate
8-oxo-7-hydrodeoxyguanosine
deoxyguanosine triphosphate

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair. / Sheng, Zijing; Oka, Sugako; Tsuchimoto, Daisuke; Abolhassani, Nona; Nomaru, Hiroko; Kunihiko, Sakumi; Yamada, Hidetaka; Nakabeppu, Yusaku.

In: Journal of Clinical Investigation, Vol. 122, No. 12, 03.12.2012, p. 4344-4361.

Research output: Contribution to journalArticle

Sheng, Zijing ; Oka, Sugako ; Tsuchimoto, Daisuke ; Abolhassani, Nona ; Nomaru, Hiroko ; Kunihiko, Sakumi ; Yamada, Hidetaka ; Nakabeppu, Yusaku. / 8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 12. pp. 4344-4361.
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