MUTYH promotes oxidative microglial activation and inherited retinal degeneration.
MUTYH promotes oxidative microglial activation and inherited retinal degeneration.
复制标题
DOI：
10.1172/jci.insight.87781
复制
发表时间：
2016-09
期刊：
影响因子：
8
通讯作者：
S. Nakatake;Y. Murakami;Y. Ikeda;N. Morioka;Takashi Tachibana;Kohta Fujiwara;Noriko Yoshida;Shoji Notomi;T. Hisatomi;S. Yoshida;T. Ishibashi;Y. Nakabeppu;K. Sonoda
中科院分区：
文献类型：
--
作者：
S. Nakatake;Y. Murakami;Y. Ikeda;N. Morioka;Takashi Tachibana;Kohta Fujiwara;Noriko Yoshida;Shoji Notomi;T. Hisatomi;S. Yoshida;T. Ishibashi;Y. Nakabeppu;K. Sonoda
氧化应激与多种神经退行性疾病有关，包括色素性视网膜炎（RP），这是一种导致失明的遗传性疾病。氧化应激介导神经元细胞死亡的生物学和细胞机制在很大程度上尚不清楚。在 RP 小鼠模型（rd10 小鼠）中，我们发现氧化 DNA 损伤通过 MutY 同源物介导（MUYTH 介导）碱基切除修复（BER）激活小胶质细胞，从而加剧视网膜炎症和变性。在视网膜变性的早期阶段，氧化性 DNA 损伤在小胶质细胞中积累，导致单链断裂 (SSB) 和聚 (ADP-核糖) 聚合酶激活。相比之下，rd10 小鼠的 Mutyh 缺陷阻止了小胶质细胞中 SSB 的形成，从而抑制了小胶质细胞的激活和感光细胞死亡。此外，Mutyh 缺陷的原代小胶质细胞减弱了氧化应激下炎症和细胞毒性表型的极化。因此，MUTYH 介导的氧化小胶质细胞激活中的 BER 可能是抑制 RP 和其他与氧化应激相关的神经退行性疾病疾病进展的新靶点。
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.