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 8

Mutyh-KO mice are resistant to 3-NP–induced motor impairment and mitochondrial degeneration.

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Mutyh-KO mice are resistant to 3-NP–induced motor impairment and mitoch...
(A) Expression of MUTYH in mouse striatum. MUTYH IRs were detected in WT but not Mutyh-KO brains. Scale bar: 25 μm. (B) MUTYH IRs were mostly detected in cytoplasm of DARPP32-positive cells in WT striatum. Scale bar: 10 μm. (C) Immunoelectron microscopy for MUTYH in WT striatum. C, cytoplasm; N, nucleus; M, mitochondrion. Scale bar: 250 nm. (D) MUTYH IR was detected in either cytoplasm or nuclei of F4/80-positive WT microglia. Scale bar: 10 μm. (E) Resistance of Mutyh-KO mice to 3-NP–induced motor impairment. Mutyh-KO mice exhibited a higher incidence of rearing in the open filed test after 3-NP exposure for 7 days than did WT mice. WT (PBS, n = 6; 3-NP 120 mg/kg/d, n = 10; 3-NP 150 mg/kg/d, n = 10); Mutyh-KO (PBS, n = 7; 3-NP 120 mg/kg/d, n = 5; 3-NP 150 mg/kg/d, n = 10). (F) Mitochondrial degeneration in striatum induced by 3-NP. Electron microscopy revealed disruption of outer and inner membranes (arrows) and cristae (arrowheads) in striatal mitochondria of WT but not Mutyh-KO mice (3-NP, 150 mg/kg/d, for 7 days). Scale bar: 200 nm. (G) Mitochondrial function was maintained in Mutyh-KO mice after 3-NP administration. Mitochondrial function was examined by histochemical detection of cytochrome oxidase activity. Images were obtained by DIC microscopy. WT (PBS, n = 4; 3-NP, n = 4); Mutyh-KO (PBS, n = 5; 3-NP, n = 5). Scale bar: 20 μm. In E and G (right), data are shown as LS means ± SEM. Levels not connected with the same letter are significantly different (Student’s t test). *P, compared with the corresponding WT sample.