MutT Homolog-1 Attenuates Oxidative DNA Damage and Delays Photoreceptor Cell Death in Inherited Retinal Degeneration

Yusuke Murakami, Yasuhiro Ikeda, Noriko Yoshida, Shoji Notomi, Toshio Hisatomi, Sugako Oka, Gabriele De Luca, Yoshikazu Yonemitsu, Margherita Bignami, Yusaku Nakabeppu, Tatsuro Ishibashi

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Retinitis pigmentosa (RP) is a genetically heterogenous group of inherited retinal degenerative diseases resulting from photoreceptor cell death and affecting >1 million persons globally. Although oxidative stress has been implicated in the pathogenesis of RP, the mechanisms by which oxidative stress mediates photoreceptor cell death are largely unknown. Here, we show that oxidation of nucleic acids is a key component in the initiation of death-signaling pathways in rd10 mice, a model of RP. Accumulation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) increased in photoreceptor cells, and especially within their nuclei, in rd10 mice as well as in Royal College of Surgeons rats, another model of RP caused by different genetic mutations. Vitreous samples from humans with RP contained higher levels of 8-oxo-dG excreted than samples from nondegenerative controls. Transgenic overexpression of human MutT homolog-1, which hydrolyzes oxidized purine nucleoside triphosphates in the nucleotide pool, significantly attenuated 8-oxo-dG accumulation in nuclear DNA and photoreceptor cell death in rd10 mice, in addition to suppressing DNA single-strand break formation, poly(ADP-ribose) polymerase activation, and nuclear translocation of apoptosis-inducing factor. These findings indicate that oxidative DNA damage is an important process for the triggering of photoreceptor cell death in rd10 mice and suggest that stimulation of DNA repair enzymes may be a novel therapeutic approach to attenuate photoreceptor cell loss in RP.

Original languageEnglish
Pages (from-to)1378-1386
Number of pages9
JournalAmerican Journal of Pathology
Volume181
Issue number4
DOIs
Publication statusPublished - Oct 1 2012

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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