Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14598-603. doi: 10.1073/pnas.1206937109. Epub 2012 Aug 20.
Retinitis pigmentosa comprises a group of inherited retinal photoreceptor 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 nonautonomous 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.
色素性视网膜炎是一组遗传性视网膜光感受器退行性疾病，导致视力逐渐丧失。尽管在大多数情况下，杆细胞而不是锥细胞携带有害的基因突变，但在这种疾病中，锥细胞确实会死亡，通常在主杆细胞丧失阶段之后。杆状光感受器死亡的特征是凋亡特征。相比之下，随后的非自主锥细胞死亡的机制和特征在很大程度上仍然未知。在这项研究中，我们表明，受体相互作用蛋白（RIP）激酶介导 rd10 小鼠中的坏死锥细胞死亡，rd10 小鼠是一种由杆状细胞特异性基因突变引起的色素性视网膜炎模型。程序性坏死的关键调节因子 RIP3 的表达在 rd10 小鼠视网膜中在锥细胞而非杆细胞退化的阶段升高。尽管缺乏 Rip3 的 rd10 小鼠表现出与对照 rd10 小鼠相当的杆状细胞退化，但它们显示出显著的锥状细胞保存。rd10 小鼠视网膜的超微结构分析表明，大量死亡的锥细胞表现出坏死形态，这可以通过 Rip3 缺乏来挽救。此外，RIP 激酶抑制剂的药物治疗减轻了 rd10 小鼠中锥细胞的组织学和功能缺陷。因此，涉及 RIP 激酶的坏死机制在遗传性视网膜变性中的锥细胞死亡中至关重要，这表明 RIP 激酶途径是保护色素性视网膜炎患者锥细胞介导的中心和周边视力丧失的潜在靶点。
