Document Detail


8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair.
MedLine Citation:
PMID:  23143307     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-12
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-03     Completed Date:  2013-02-04     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4344-61     Citation Subset:  AIM; IM    
Affiliation:
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis Inducing Factor / metabolism
Benzamides / pharmacology
Calpain / antagonists & inhibitors,  metabolism
Cell Nucleus / metabolism
Corpus Striatum / pathology
DNA Breaks, Single-Stranded
DNA Glycosylases / genetics,  metabolism,  physiology*
DNA Repair*
DNA, Mitochondrial / genetics
Dipeptides / pharmacology
Guanine / analogs & derivatives*,  metabolism,  physiology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microglia / metabolism
Mitochondria / metabolism
Motor Activity
Neurodegenerative Diseases / etiology,  metabolism*,  pathology
Nitro Compounds
Oxidative Stress*
Phosphoric Monoester Hydrolases / genetics
Poly(ADP-ribose) Polymerases / antagonists & inhibitors,  metabolism
Propionates
Chemical
Reg. No./Substance:
0/Apoptosis Inducing Factor; 0/Benzamides; 0/DNA, Mitochondrial; 0/Dipeptides; 0/Nitro Compounds; 0/Pdcd8 protein, mouse; 0/Propionates; 3544-24-9/3-aminobenzamide; 504-88-1/3-nitropropionic acid; 5614-64-2/8-hydroxyguanine; 73-40-5/Guanine; 88191-84-8/calpain inhibitor III; EC 2.4.2.30/Parp1 protein, mouse; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.1.6.-/MTH1 protein, mouse; EC 3.2.2.-/DNA Glycosylases; EC 3.2.2.-/Ogg1 protein, mouse; EC 3.2.2.-/mutY adenine glycosylase; EC 3.4.22.-/Calpain
Comments/Corrections

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