title: MUTYH promotes oxidative microglial activation and inherited retinal degeneration.
abstract: Oxidative stress is implicated in various neurodegenerative disorders, including retinitis pigmentosa (RP), an inherited disease that causes blindness. The biological and cellular mechanisms by which oxidative stress mediates neuronal cell death are largely unknown. In a mouse model of RP (rd10 mice), we show that oxidative DNA damage activates microglia through MutY homolog-mediated (MUYTH-mediated) base excision repair (BER), thereby exacerbating retinal inflammation and degeneration. In the early stage of retinal degeneration, oxidative DNA damage accumulated in the microglia and caused single-strand breaks (SSBs) and poly(ADP-ribose) polymerase activation. In contrast,Mutyhdeficiency in rd10 mice prevented SSB formation in microglia, which in turn suppressed microglial activation and photoreceptor cell death. Moreover,Mutyh-deficient primary microglial cells attenuated the polarization to the inflammatory and cytotoxic phenotype under oxidative stress. Thus, MUTYH-mediated BER in oxidative microglial activation may be a novel target to dampen the disease progression in RP and other neurodegenerative disorders that are associated with oxidative stress.
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Nakatake
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Morioka
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tachibana
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.|Department of Ophthalmology, Graduate School of Medical Sciences, Akita University, Hondo, Akita, Japan.
authors.forename: Kohta
authors.initials: K
authors.lastname: Fujiwara
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Notomi
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Hisatomi
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishibashi
authors.affiliation: Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Nakabeppu
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
authors.forename: Koh-Hei
authors.initials: KH
authors.lastname: Sonoda
mesh_terms: D000818:Animals; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D018384:Oxidative Stress; D012162:Retinal Degeneration / Q000473:pathology*; D012174:Retinitis Pigmentosa
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase