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 11

Molecular mechanisms underlying 8-oxoG–induced striatal degeneration.

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Molecular mechanisms underlying 8-oxoG–induced striatal degeneration. Ch...
Chronic administration of the mitochondrial neurotoxin 3-NP to mutant mice lacking OGG1, which excises a major oxidative base lesion 8-oxoG (GO) opposite cytosine from DNA, and/or MTH1, which hydrolyses 8-oxo–dGTP in the nucleotide pool to prevent its harmful incorporation into DNA, causes significantly increased accumulation of 8-oxoG in the striatum. At an early stage, buildup of 8-oxoG in the mitochondrial DNA of striatal MSNs causes calpain-dependent neuronal loss triggered by mitochondrial MUTYH-initiated BER of adenines opposite 8-oxoG. In the later stages, buildup of 8-oxoG in the nuclear DNA of microglia causes PARP-dependent nuclear translocation of mitochondrial AIF triggered by nuclear MUTYH-initiated BER, thus resulting in microgliosis. Two distinct pathways of cell death, both dependent on MUTYH-initiated BER (34), result in severe striatal degeneration and motor impairments.