MUTYH promotes oxidative microglial activation and inherited retinal degeneration

Shunji Nakatake, Yusuke Murakami, Yasuhiro Ikeda, Noriko Morioka, Takashi Tachibana, Kohta Fujiwara, Noriko Yoshida, Shoji Notomi, Toshio Hisatomi, Shigeo Yoshida, Tatsuro Ishibashi, Yusaku Nakabeppu, Koh Hei Sonoda

Research output: Contribution to journalArticle

9 Citations (Scopus)

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, 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.

Original languageEnglish
Article numbere87781
JournalJCI Insight
Volume1
Issue number15
DOIs
Publication statusPublished - Jan 1 2016

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Retinal Degeneration
Retinitis Pigmentosa
Microglia
Oxidative Stress
DNA Repair
Neurodegenerative Diseases
DNA Damage
Cell Death
Photoreceptor Cells
Poly(ADP-ribose) Polymerases
Blindness
Disease Progression
Inflammation
Phenotype

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

MUTYH promotes oxidative microglial activation and inherited retinal degeneration. / Nakatake, Shunji; Murakami, Yusuke; Ikeda, Yasuhiro; Morioka, Noriko; Tachibana, Takashi; Fujiwara, Kohta; Yoshida, Noriko; Notomi, Shoji; Hisatomi, Toshio; Yoshida, Shigeo; Ishibashi, Tatsuro; Nakabeppu, Yusaku; Sonoda, Koh Hei.

In: JCI Insight, Vol. 1, No. 15, e87781, 01.01.2016.

Research output: Contribution to journalArticle

Nakatake, S, Murakami, Y, Ikeda, Y, Morioka, N, Tachibana, T, Fujiwara, K, Yoshida, N, Notomi, S, Hisatomi, T, Yoshida, S, Ishibashi, T, Nakabeppu, Y & Sonoda, KH 2016, 'MUTYH promotes oxidative microglial activation and inherited retinal degeneration', JCI Insight, vol. 1, no. 15, e87781. https://doi.org/10.1172/jci.insight.87781
Nakatake, Shunji ; Murakami, Yusuke ; Ikeda, Yasuhiro ; Morioka, Noriko ; Tachibana, Takashi ; Fujiwara, Kohta ; Yoshida, Noriko ; Notomi, Shoji ; Hisatomi, Toshio ; Yoshida, Shigeo ; Ishibashi, Tatsuro ; Nakabeppu, Yusaku ; Sonoda, Koh Hei. / MUTYH promotes oxidative microglial activation and inherited retinal degeneration. In: JCI Insight. 2016 ; Vol. 1, No. 15.
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