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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Receptor interacting protein kinase mediates necrotic cone but not rod cell death in a mouse model of inherited degeneration
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Receptor interacting protein kinase mediates necrotic cone but not rod cell death in a mouse model of inherited degeneration

机译：受体相互作用的蛋白激酶在遗传性退化的小鼠模型中介导坏死锥体而不是杆状细胞死亡

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摘要

Retinitis pigmentosa comprises a group of inherited retinal photore-ceptor degenerations that lead to progressive loss of vision. Although in most cases rods, but not cones, harbor the deleterious gene mutations, cones do die in this disease, usually after the main phase of rod cell loss. Rod photoreceptor death is characterized by apoptotic features. In contrast the mechanisms and features of subsequent non-autonomous cone cell death remain largely unknown. In this study, we show that receptor-interacting protein (RIP) kinase mediates necrotic cone cell death in rd10 mice, a mouse model of retinitis pigmentosa caused by a mutation in a rod-specific gene. The expression of RIP3, a key regulator of programmed necrosis, was elevated in rd10 mouse retinas in the phase of cone but not rod degeneration. Although rd10 mice lacking Rip3 developed comparable rod degeneration to control rd10 mice, they displayed a significant preservation of cone cells. Ultrastructural analysis of rd10 mouse retinas revealed that a substantial fraction of dying cones exhibited necrotic morphology, which was rescued by Rip3 deficiency. Additionally, pharmacologic treatment with a RIP kinase inhibitor attenuated histological and functional deficits of cones in rd10 mice. Thus, necrotic mechanisms involving RIP kinase are crucial in cone cell death in inherited retinal degeneration, suggesting the RIP kinase pathway as a potential target to protect cone-mediated central and peripheral vision loss in patients with retinitis pigementosa.
机译：色素性视网膜炎包括一组遗传性视网膜光感受器变性，导致视力进行性丧失。尽管在大多数情况下杆状细胞而不是视锥细胞具有有害的基因突变，视锥细胞确实在这种疾病中死亡，通常是在视杆细胞丧失的主要阶段之后。杆感光细胞死亡的特征是凋亡特征。相反，随后的非自主视锥细胞死亡的机制和特征仍然未知。在这项研究中，我们表明受体相互作用蛋白（RIP）激酶介导rd10小鼠坏死锥体细胞死亡，这是一种由视杆特异性基因突变引起的色素性视网膜炎的小鼠模型。 RIP3是程序性坏死的关键调节因子，在视锥细胞阶段的rd10小鼠视网膜中表达升高，但未发生杆变性。尽管缺少Rip3的rd10小鼠发育出与控制rd10小鼠相当的视杆变性，但它们显示了显着的视锥细胞保存。对rd10小鼠视网膜的超微结构分析表明，垂死的视锥细胞大部分显示出坏死的形态，并通过Rip3缺乏得以挽救。此外，用RIP激酶抑制剂进行药理治疗可减轻rd10小鼠视锥细胞的组织学和功能缺陷。因此，涉及RIP激酶的坏死机制对于遗传性视网膜变性中视锥细胞死亡至关重要，提示RIP激酶途径是保护色素性视网膜炎患者视锥介导的中枢和周围视力丧失的潜在靶标。

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  • 作者

    Yusuke Murakami; Hidetaka Matsumoto; Miin Roh; Jun Suzuki; Toshio Hisatomi; Yasuhiro lkeda; Joan W. Miller; Demetrios G. Vavvas;

  • 作者单位

    Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114;

    Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114;

    Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114;

    Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114;

    Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;

    Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;

    Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114;

    Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    apoptosis; neurodegeneration; neuroprotection; oxidation; inflammation;

    机译：细胞凋亡神经变性神经保护氧化炎;

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