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
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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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 4

Oxidative DNA damage targeted microglia in early phase of retinal degeneration in rd10 mice.

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Oxidative DNA damage targeted microglia in early phase of retinal degene...
(A and B) Iba-1 (green) and 8-oxoG (red) staining in the retinas of P17 (A) and P21 (B) rd10;Mutyh+/+ mice or rd10;Mutyh−/− mice. (A) Part of 8-oxoG signals were colocalized in Iba-1–positive microglia in the retinas of the rd10;Mutyh+/+ mice and rd10;Mutyh−/− mice at P17. Scale bar: 20 μm. (B) Increased 8-oxoG accumulation was observed in the photoreceptor layer, as well as microglial cells in rd10;Mutyh+/+ mice at P21, whereas they were substantially prevented in the retinas of rd10;Mutyh−/− mice. The arrows indicate colocalization of Iba-1–positive microglia and 8-oxoG. The arrowheads indicate the cells positive for 8-oxoG but negative for Iba-1. Scale bar: 20 μm. (C) Iba-1 (green), 8-oxoG (red), and DAPI (blue) staining in the retinas of P21 rd10;Mutyh+/+ mice. Part of 8-oxoG signal was colocalized in the nuclear of Iba-1–positive microglia in the retina of rd10;Mutyh+/+ mice at P21. Scale bar: 5 μm. All samples in this figure were treated with 2 N HCl (HCl+) to enhance the 8-oxoG signal in nuclear DNA. Figures show the representative results from 3 experiments.