Photoreceptor dysfunction associated with rhodopsin mislocalization

标题：与视紫红质错误定位相关的光感受器功能障碍 摘要： 视紫红质错误定位在各种致盲性疾病中观察到，包括综合征和 非综合征性视网膜色素变性在大多数这些疾病中，视紫红质错误定位于 内节（IS）质膜（PM）。越来越多的证据表明，PM 视紫红质的错误定位是光感受器变性的根本原因，但如何 错误定位导致视杆细胞变性仍然是未知的。在这个项目中，我们将 测试错误定位的视紫红质破坏PM体内平衡从而导致 视杆细胞感光神经元的功能障碍和变性。在视杆细胞中，视紫红质是 以极高的速率合成并输送到外节（OS）的基部。 这种高合成速率与高催化速率相平衡。含视紫红质的盘 膜在OS的尖端脱落，被视网膜色素吞噬和消化 上皮（RPE）细胞。当视紫红质错误定位时，大量的视紫红质被递送 到IS的PM，其中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积极消除， 而新的视紫红质分子不断地被输送到这个结构。的 消除机制将是本研究的主题（目的1）。感光细胞 终末分化的神经元，在脊椎动物的整个生命周期中存活，包括 人类因此，感光细胞的内容物必须不断更新。这如何 更新发生的OS结构是公认的，但尚未研究的IS。我们 将解决更新机制的IS PM蛋白质在杆光感受器和调查 通过大量误作用破坏IS PM蛋白体内平衡的病理过程 视紫红质（Aim 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).