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Published on: October 27, 2017
MUTYH promotes oxidative microglial activation and inherited retinal degeneration
Shunji Nakatake1, Yusuke Murakami1, Yasuhiro Ikeda1
1Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka, Japan.
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.
Insights
Oxidative stress drives neurodegeneration in retinitis pigmentosa (RP). Targeting MUTYH-mediated DNA repair in microglia reduces inflammation and photoreceptor cell death, offering a new therapeutic strategy for RP and related disorders.
Area of Science:
- Neuroscience
- Genetics
- Ophthalmology
Background:
- Oxidative stress contributes to neurodegenerative diseases like retinitis pigmentosa (RP).
- The precise mechanisms linking oxidative stress to neuronal death in RP remain unclear.
- Microglial activation plays a role in retinal inflammation and degeneration.
Purpose of the Study:
- To investigate the role of MUTYH-mediated base excision repair (BER) in microglial activation during RP.
- To determine if inhibiting MUTYH can mitigate retinal degeneration in a mouse model of RP.
- To explore MUTYH as a potential therapeutic target for RP and other oxidative stress-related neurodegenerative disorders.
Main Methods:
- Utilized the rd10 mouse model of retinitis pigmentosa (RP).
- Assessed oxidative DNA damage, single-strand breaks (SSBs), and poly(ADP-ribose) polymerase (PARP) activation in retinal microglia.
- Examined the effects of Mutyh deficiency on microglial activation and photoreceptor cell survival.
- Investigated Mutyh-deficient primary microglial cell responses to oxidative stress.
Main Results:
- Oxidative DNA damage activates microglia via MUTYH-mediated BER in rd10 mice, worsening retinal degeneration.
- Mutyh deficiency prevented SSB formation in microglia, suppressed microglial activation, and reduced photoreceptor cell death.
- Mutyh-deficient microglia showed attenuated inflammatory and cytotoxic polarization under oxidative stress.
- MUTYH-mediated BER is identified as a key pathway in oxidative microglial activation.
Conclusions:
- MUTYH-mediated base excision repair is a critical driver of microglial activation and subsequent retinal degeneration in RP.
- Targeting MUTYH offers a promising therapeutic strategy to reduce inflammation and protect photoreceptor cells in RP.
- This research provides a novel target for treating neurodegenerative disorders associated with oxidative stress.
