Photoreceptor dysfunction associated with rhodopsin mislocalization

标题：与视紫质定位错误相关的光感受器功能障碍 摘要： 视紫红质定位错误在各种致盲障碍中观察到，包括综合征和 非综合征性视网膜色素变性。在大多数这些障碍中，视紫红质错误地定位于 内段(IS)质膜(PM)。越来越多的证据表明，首相 视紫红质的错误定位是光感受器退化的根本原因，但这是如何发生的 定位错误导致视杆感光细胞变性仍不清楚。在这个项目中，我们将 验证错误定位的视紫红质破坏PM动态平衡从而导致 视杆感光神经元功能障碍和变性。在杆状感光器中，视紫红质是 以极高的速度合成并输送到外部节段的底部(OSS)。 这种高合成速率与高分解新陈代谢速率是平衡的。含有视紫红质的盘 膜在OSS的顶端脱落，被视网膜色素吞噬和消化。 上皮(RPE)细胞。当视紫红质定位错误时，就会产生大量的视紫红质 到国际空间站的PM，在那里含有视紫红质的膜与 RPE细胞。然而，我们最近发现，错误定位的视紫红质被主动消除 而新的视紫红质分子不断地输送到这个结构中。这个 消除机制将是本研究的主题(目标1)。光感受器细胞 在脊椎动物的整个生命周期中存活的终末分化神经元，包括 人类。因此，光感受器细胞的内容必须不断更新。这是怎么回事 更新发生在操作系统结构完善的情况下，但尚未针对IS进行研究。我们 将阐述杆状感光细胞中IS PM蛋白的更新机制，并研究 大量失误破坏IS PM蛋白动态平衡的病理过程 视紫红质在那里(目标2)。

Title: Photoreceptor dysfunction associated with rhodopsin mislocalization Abstract: Rhodopsin mislocalization is observed in various blinding disorders including syndromic and non-syndromic retinitis pigmentosa. In most of these disorders rhodopsin mislocalizes to the inner segment (IS) plasma membrane (PM). Growing evidence suggests that PM mislocalization of rhodopsin is the root cause of photoreceptor degeneration, but how such mislocalization causes rod photoreceptor degeneration remains unknown. In this project, we will test the hypothesis that mislocalized rhodopsin disrupts PM homeostasis thereby causing dysfunction and degeneration of rod photoreceptor neurons. In rod photoreceptors, rhodopsin is synthesized at an extremely high rate and delivered to the base of the outer segments (OSs). This high rate of synthesis is balanced with a high rate of catabolism. Rhodopsin-containing disk membranes are shed at the tip of the OSs, engulfed, and digested by the retinal pigment epithelial (RPE) cells. When rhodopsin mislocalizes, a massive amount of rhodopsin is delivered to the PM of the ISs, where rhodopsin-containing membranes have no apparent contact with RPE cells. Nevertheless, we recently found that mislocalized rhodopsin is actively eliminated from the PM while new rhodopsin molecules are continuously delivered to this structure. The mechanism of elimination will be the subject of this study (Aim 1). Photoreceptor cells are terminally differentiated neurons that survive during the entire lifespan of vertebrates, including humans. Therefore, the contents of photoreceptor cells must be continuously renewed. How this renewal occurs for the OS structure is well-established, but has not been studied for the IS. We will address the renewal mechanism of IS PM proteins in rod photoreceptors and investigate the pathological process of disrupting the IS PM protein homeostasis by massive mistrafficking of rhodopsin there (Aim 2).