TY - JOUR
T1 - MUTYH promotes oxidative microglial activation and inherited retinal degeneration
AU - Nakatake, Shunji
AU - Murakami, Yusuke
AU - Ikeda, Yasuhiro
AU - Morioka, Noriko
AU - Tachibana, Takashi
AU - Fujiwara, Kohta
AU - Yoshida, Noriko
AU - Notomi, Shoji
AU - Hisatomi, Toshio
AU - Yoshida, Shigeo
AU - Ishibashi, Tatsuro
AU - Nakabeppu, Yusaku
AU - Sonoda, Koh Hei
N1 - Funding Information:
We thank M.R. Al-Ubaidi (University of Oklahoma Health Sciences Center) and H. Hara (Gifu Pharmaceutical University, Gifu, Japan) for providing 661W cells and M. Arima and M. Kumano (Kyushu University) for their technical support for the experiments. We also appreciate K. Sakumi, S. Oka, and D. Tsuchimoto (Kyushu University) for the scientific discussions. This work was supported by the Japanese Ministry of Education, Culture, Sports, Science, and Technology, grants 25861637 (to YM) and 22221004 (to YN); a Japan Intractable Disease Research Foundation grant (to YM); a Japanese Retinitis Pigmentosa Society grant (to YM); a Rhoto Award grant (to YI); and a Takeda Science Foundation grant (to YI).
Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016
Y1 - 2016
N2 - 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, Mutyh deficiency 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.
AB - 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, Mutyh deficiency 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.
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U2 - 10.1172/jci.insight.87781
DO - 10.1172/jci.insight.87781
M3 - Article
C2 - 27699246
AN - SCOPUS:85055608702
VL - 1
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 15
M1 - e87781
ER -