title: MutT homolog-1 attenuates oxidative DNA damage and delays photoreceptor cell death in inherited retinal degeneration.
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.
authors: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Yusuke
authors: Y
authors: Murakami
authors: Yasuhiro
authors: Y
authors: Ikeda
authors: Noriko
authors: N
authors: Yoshida
authors: Shoji
authors: S
authors: Notomi
authors: Toshio
authors: T
authors: Hisatomi
authors: Sugako
authors: S
authors: Oka
authors: Gabriele
authors: G
authors: De Luca
authors: Yoshikazu
authors: Y
authors: Yonemitsu
authors: Margherita
authors: M
authors: Bignami
authors: Yusaku
authors: Y
authors: Nakabeppu
authors: Tatsuro
authors: T
authors: Ishibashi
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction
chemical_list: D051033:Apoptosis Inducing Factor; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases; D010744:Phosphoric Monoester Hydrolases; D002154:Calpain; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes