title: 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.affiliation: Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Zijing
authors.initials: Z
authors.lastname: Sheng
authors.forename: Sugako
authors.initials: S
authors.lastname: Oka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuchimoto
authors.forename: Nona
authors.initials: N
authors.lastname: Abolhassani
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nomaru
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Sakumi
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yamada
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003342:Corpus Striatum / Q000473:pathology; D053904:DNA Breaks, Single-Stranded; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics; D004151:Dipeptides / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009043:Motor Activity; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009574:Nitro Compounds; D018384:Oxidative Stress; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011422:Propionates
chemical_list: D051033:Apoptosis Inducing Factor; D001549:Benzamides; D004272:DNA, Mitochondrial; D004151:Dipeptides; D009574:Nitro Compounds; C494830:AIFM1 protein, mouse; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011422:Propionates; C024829:8-hydroxyguanine; D006147:Guanine; C025160:3-aminobenzamide; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D010744:Phosphoric Monoester Hydrolases; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C061738:mutY adenine glycosylase; D002154:Calpain; C509779:Nudt1 protein, mouse; C015392:3-nitropropionic acid; C058076:calpain inhibitor III