Expression of 8-oxoguanine DNA glycosylase (OGG1) in Parkinson?s disease and related neurodegenerative disorders

Fukae, Jiro; Takanashi, Masashi; Kubo, S.; Nishioka, Ken Ichi; Nakabeppu, Yusaku; Mori, Hideo; Mizuno, Yoshikuni; Hattori, Nobutaka

doi:10.1007/s00401-004-0937-9

Cited by 125 publications

(82 citation statements)

References 31 publications

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“…9 Furthermore, we recently also found a highly increased expression of a mitochondrial form of OGG1 (hOGG1-2a) in dopamine neurons in the SN of PD patient brain, thus supporting our hypothesis that 8-oxoG accumulated in mitochondrial DNA is somehow toxic to dopamine neurons. 30 The present study strongly suggests that the increased expression of MTH1 in the dopamine neurons of PD patients may attenuate their progressive degeneration, and an experimental demonstration of this hypothesis would shed light on the development of new strategies for the therapeutic treatment of PD.…”

Section: Discussionmentioning

confidence: 57%

MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

et al. 2005

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We previously reported that 8-oxoguanine (8-oxoG) accumulates in the cytoplasm of dopamine neurons in the substantia nigra of patients with Parkinson's disease and the expression of MTH1 carrying an oxidized purine nucleoside triphosphatase activity increases in these neurons, thus suggesting that oxidative damage in nucleic acids is involved in dopamine neuron loss. In the present study, we found that levels of 8-oxoG in cellular DNA and RNA increased in the mouse nigrostriatal system during the tyrosine hydroxylase (TH)-positive dopamine neuron loss induced by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MTH1-null mice exhibited a greater accumulation of 8-oxoG in mitochondrial DNA accompanied by a more significant decrease in TH and dopamine transporter immunoreactivities in the striatum after MPTP administration, than in wild-type mice. We thus demonstrated that MTH1 protects the dopamine neurons from oxidative damage in the nucleic acids, especially in the mitochondrial DNA of striatal nerve terminals of dopamine neurons.

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Section: Discussionmentioning

confidence: 57%

MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

et al. 2005

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“…We and others have shown that an accumulation of 8-oxoG in mtDNA with increased expression of MTH1, OGG1 and MUTYH in the brains of PD and AD patients (Shimura-Miura et al, 1999;Iida et al, 2002;Fukae et al, 2005;Arai et al, 2006), and involvement of the calpain-cathepsin pathway, are implicated in various neurodegenerative disorders including PD and AD (Saito et al, 1993;Mouatt-Prigent et al, 1996). We have also demonstrated that 8-oxoG accumulation in mtDNA of striatal dopaminergic nerve terminals triggers their retrograde degeneration in a mouse model of PD (Yamaguchi et al, 2006).…”

Section: Mutyh-initiated Cell Death and Its Implication In Carcinogenmentioning

confidence: 58%

Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs

Oka

Ohno

Tsuchimoto

et al. 2008

EMBO J

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199

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Oxidative base lesions, such as 8-oxoguanine (8-oxoG), accumulate in nuclear and mitochondrial DNAs under oxidative stress, resulting in cell death. However, it is not known which form of DNA is involved, whether nuclear or mitochondrial, nor is it known how the death order is executed. We established cells which selectively accumulate 8-oxoG in either type of DNA by expression of a nuclear or mitochondrial form of human 8-oxoG DNA glycosylase in OGG1-null mouse cells. The accumulation of 8-oxoG in nuclear DNA caused poly-ADP-ribose polymerase (PARP)-dependent nuclear translocation of apoptosis-inducing factor, whereas that in mitochondrial DNA caused mitochondrial dysfunction and Ca 2 þ release, thereby activating calpain. Both cell deaths were triggered by single-strand breaks (SSBs) that had accumulated in the respective DNAs, and were suppressed by knockdown of adenine DNA glycosylase encoded by MutY homolog, thus indicating that excision of adenine opposite 8-oxoG lead to the accumulation of SSBs in each type of DNA. SSBs in nuclear DNA activated PARP, whereas those in mitochondrial DNA caused their depletion, thereby initiating the two distinct pathways of cell death.

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“…Expression levels of MTH1, OGG1, and MUTYH are also significantly altered in the brains of such patients (16,(19)(20)(21)(22), suggesting that their altered expression along with accumulation of 8-oxoG in brain cause neurodegeneration; however, how 8-oxoG and these enzymes are associated with the neurodegenerative process is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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

Sheng

Oka

Tsuchimoto³

et al. 2012

J. Clin. Invest.

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115

112

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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.

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Expression of 8-oxoguanine DNA glycosylase (OGG1) in Parkinson?s disease and related neurodegenerative disorders

Cited by 125 publications

References 31 publications

MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs

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

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