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 language | English |
|---|---|
| Article number | e87781 |
| Journal | JCI Insight |
| Volume | 1 |
| Issue number | 15 |
| DOIs | |
| Publication status | Published - Jan 1 2016 |
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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 journal › Article
}
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
PY - 2016/1/1
Y1 - 2016/1/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85055608702&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055608702&partnerID=8YFLogxK
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 -