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

被引：109

作者：

Sheng, Zijing ^{[2
]}

Oka, Sugako ^{[2
]}

Tsuchimoto, Daisuke ^{[2
]}

Abolhassani, Nona

Nomaru, Hiroko

Sakumi, Kunihiko ^{[2
]}

Yemada, Hidetaka ^{[3
]}

Nakabeppu, Yusaku ^{[1
,2
]}

机构：

[1] Kyushu Univ, Div Neurofunct Genom, Dept Immunobiol & Neurosci, Med Inst Bioregulat,Higashi Ku, Fukuoka 8128582, Japan

[2] Kyushu Univ, Res Ctr Nucleotide Pool, Fukuoka 8128582, Japan

[3] Kurume Univ, Sch Med, Cognit & Mol Res Inst Brain Dis, Kurume, Fukuoka 830, Japan

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2012年 / 122卷 / 12期

基金：

日本学术振兴会;

关键词：

PURINE NUCLEOSIDE TRIPHOSPHATASE; OXIDATIVE DAMAGE; CELL-DEATH; MITOCHONDRIAL-DNA; 3-NITROPROPIONIC ACID; NUCLEIC-ACIDS; STRIATAL DEGENERATION; HOMOLOG HMYH; EXPRESSION; DISEASE;

D O I：

10.1172/JCI65053

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 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 high:under:Conditions of oxidative stress.

引用

页码：4344 / 4361

页数：18