8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair
Zijing Sheng, … , Hidetaka Yamada, Yusaku Nakabeppu
Zijing Sheng, … , Hidetaka Yamada, Yusaku Nakabeppu
Published November 12, 2012
Citation Information: J Clin Invest. 2012;122(12):4344-4361. https://doi.org/10.1172/JCI65053.
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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 1

Mth1/Ogg1-DKO mice are extremely vulnerable to 3-NP–induced motor impairments and striatal degeneration.

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Mth1/Ogg1-DKO mice are extremely vulnerable to 3-NP–induced motor impai...
(A) MTH1 (upper left panels) and OGG1 (upper right panels) IRs (red) were abundant in WT striatum and were predominantly localized in DARPP32-positive neurons (green). Arrows show positively stained neurons. Scale bar: 20 μm. OGG1 IR (red) in the cytoplasm colocalized with HSP60 IR (green) (lower panels). Scale bar: 10 μm. (B) Motor impairments after exposure to 3-NP. Numbers of animals examined per condition are 14 (WT, PBS), 21 (WT, 3-NP), 11 (Mth1/Ogg1-DKO, PBS), and 22 (Mth1/Ogg1-DKO, 3-NP). (C) Striatal degeneration as revealed by Nissl staining. Upper panels, lower magnification; scale bar: 1 mm. Lower panels: higher magnification, scale bar: 20 μm. (D) Loss of MSNs expressing DARPP32 (green) and microgliosis as detected by F4/80 (red) staining. Arrows indicate F4/80-positive microglia. The numbers of neurons and glia in the dorsolateral striatum were counted on Nissl-stained sections, n = 3 for each group. Scale bars: 20 μm (upper); 100 μm (lower). In B and D, data in each bar graph are shown with LS means ± SEM, and P values for the effects of genotype, treatment, and interaction between genotype, and treatment are shown. Levels not connected with the same letter are significantly different (Tukey’s HSD test). *P, compared with WT mice exposed to 3-NP.