MUTYH promotes oxidative microglial activation and inherited retinal degeneration
Shunji Nakatake, … , Yusaku Nakabeppu, Koh-Hei Sonoda
Shunji Nakatake, … , Yusaku Nakabeppu, Koh-Hei Sonoda
Published September 22, 2016
Citation Information: JCI Insight. 2016;1(15):e87781. https://doi.org/10.1172/jci.insight.87781.
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Research Article Inflammation Ophthalmology

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, 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.

Authors

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

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Figure 7

MUTYH mediated the TNF-α secretion and polarization of microglia in rd10 mice.

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MUTYH mediated the TNF-α secretion and polarization of microglia in rd10...
(A) Iba-1 (green) and TNF-α (red) staining in the retinas of P21 rd10;Mutyh+/+ mice or rd10;Mutyh−/− mice. In the rd10;Mutyh+/+ mice, the microglia in retinas expressed TNF-α. In contrast, Mutyh deficiency suppressed the expression of TNF-α in microglia. (B) Iba-1 (red) and CD206 (green) staining in the retinas of P21 rd10;Mutyh+/+ mice and rd10;Mutyh−/− mice. There were few CD206-positive microglia in the retinas of the rd10;Mutyh+/+ mice. In contrast, Mutyh deficiency increased CD206-positive microglia. Scale bars: 20 μm. Figures show the representative results from 3 experiments.