PNAS：揭开感光细胞死亡之谜

研究人员首次在视网膜色素变性RP动物模型中确定了视锥感光细胞的死亡模式，并指出RIP激酶通路能够作为治疗视网膜色素变性失明患者的靶点。该文章发表在八月二十日的Proceedings of the National Academy of Sciences Early Edition杂志上。

　　

生物通报道：哈佛附属的麻省总医院眼耳专科血管生成实验室的研究人员，首次在视网膜色素变性RP动物模型中确定了视锥感光细胞的死亡模式。由哈佛医学院眼科教授麻省总医院眼科主任Joan W. Miller和Demetrios G. Vavvas博士领导的这项研究，进一步指出RIP激酶通路能够作为治疗视网膜色素变性失明患者的靶点。该文章发表在八月二十日的Proceedings of the National Academy of Sciences Early Edition杂志上。

视网膜色素变性RP是一种遗传性疾病，该疾病中眼部“视杆”和“视锥”感光细胞退化最终导致无法逆转的失明。视杆负责夜视，而视锥负责日间和中心视力。视网膜色素变性造成的失明通常开始于视杆细胞死亡夜视能力丧失，随后由于视杆和视锥细胞死亡导致外周和中心视力丧失。这种失明会给人们的日常生活带来极大的不变，例如影响他们阅读或者开车的能力。在世界范围约有一百万视网膜色素变性患者。

麻省总医院眼耳专科的视网膜退化研究显示，补充维生素A和多吃富含omega-3的食物能够延缓RP引起的视力下降，不过并不能完全停止疾病进程。绝大多数RP患者最终都会无可避免的失明。

此前有研究鉴定了引起RP的50个致病基因突变，但未能确定视杆和视锥细胞死亡的机制。许多致病基因产生的蛋白特异性用于视杆细胞，而在视杆细胞退化后，未使用这些突变蛋白的视锥细胞的死亡原因和方式还是一个迷。研究人员在RP动物模型中首次发现，RIP激酶介导的坏死涉及了感光细胞的死亡和视锥退化，并且RIP激酶缺乏会减少视锥细胞的损失。此外，研究人员还发现用抑制RIP激酶的药物进行治疗，能够显著延缓视锥细胞死亡保护感光细胞。

“尽管我们还并不清楚RIP激酶诱导坏死的详细机制，但我们发现这种坏死会导致视锥细胞死亡，有助于我们进一步了解这种疾病，更重要的是能进一步帮助我们为失明的患者提供新的治疗手段，”Vavvas博士说。

（生物通编辑：叶予）

生物通推荐原文摘要：

Receptor interacting protein kinase mediates necrotic cone but not rod cell death in a mouse model of inherited degeneration

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.