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

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

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.

Authors

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

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Figure 9

MUTYH deficiency ameliorates 3-NP–induced motor impairments and striatal degeneration in Ogg1-KO mice.

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MUTYH deficiency ameliorates 3-NP–induced motor impairments and striatal...
(A) MUTYH deficiency ameliorates 3-NP–induced motor impairments in Ogg1-KO mice. Ogg1/Mutyh-DKO mice exhibited better performances in the open-field test after exposure to 3-NP for 7 days than did Ogg1-KO mice. Ogg1-KO (PBS, n = 7; 3-NP, n = 8); Ogg1/Mutyh-DKO (PBS, n = 6; 3-NP, n = 7). (B) MUTYH deficiency suppresses striatal degeneration. Nissl staining (left panels). DARPP32-positive MSNs (center panels). F4/80-positive microglia (3,3′-diaminobenzidine/nickel staining, right panels). Scale bar: 1 mm (left); 50 μm (center); 50 μm (right). (C) The numbers of neurons and glial cells in the dorsolateral striatum with or without 3-NP exposure for 7 days. Cells were counted in Nissl-stained sections, n = 3 for each group. Data are shown as LS means ± SEM. Levels not connected with the same letter are significantly different. *P, compared with Ogg1-KO mice exposed to 3-NP.