Photoreceptor Disk Formation and Retinal Degenerations

项目概要/摘要 分子神经科学和细胞生物学中最基本的过程之一是正确组装 信号转导膜，包括蛋白质成分的运输和分选。的主要原因 视网膜变性和其他遗传性疾病是蛋白质和组织的不适当定位， 脂质。本研究的总体目标是了解参与调节的细胞机制， 支持蛋白质和细胞器定位以及感光盘形成的细胞骨架网络。 在感光盘中发现的编码蛋白质的基因的突变经常诱导异常盘形成 导致视网膜变性并表现为致盲性疾病，如视网膜色素变性或Leber's 先天性黑蒙我们的长期目标是了解极化光感受器所需的机制， 细胞生长和维持，这两个过程需要蛋白质穿过纤毛运输。我们最近 发现在增殖或分裂细胞中，细胞核分布蛋白是动力蛋白介导的运动的调节因子， C（NUDC）在光感受器盘的组装和维护中具有关键作用。这是一个新的角色， 有丝分裂后非运动感光细胞中的发育蛋白。我们的初步结果有力地表明 NUDC参与调节和维持F-actin结构的分子途径， 盘状结构，包括蛋白质cofilin 1和热休克蛋白90（HSP 90）。我们的数据显示，NUDC调节 cofilin 1（CFL 1），以维持磁盘结构所需的F-肌动蛋白架构。我们的初步数据还显示 NUDC影响线粒体的大小和在视杆细胞内段的定位，最有可能是由于 NUDC对这些细胞中微管网络的调节。此外，我们还发现了NUDC的一个新作用， 作为视网膜变性的神经保护剂，最有可能通过抑制HSP 90。

Project Summary/Abstract One of the most fundamental processes in molecular neuroscience and cell biology is the proper assembly of signal-transducing membranes including the transport and sorting of protein components. A major cause of retinal degenerations and other inherited disorders is the improper localization of proteins and organization of lipids. The overall goal of this study is to understand the cellular mechanisms involved in regulation of the cytoskeletal network that underpins protein and organelle localization and photoreceptor disk formation. Mutations in genes encoding proteins found in photoreceptor disks often induce abnormal disk formation resulting in retinal degeneration and manifest as blinding diseases such as retinitis pigmentosa or Leber’s congenital amaurosis. Our long-term goal is to understand the mechanisms required for polarized photoreceptor cell growth and maintenance, two processes that require protein trafficking across the cilium. We have recently found that a regulator of dynein-mediated movement in proliferating or dividing cells, nuclear distribution protein C (NUDC), has a critical function in photoreceptor disk assembly and maintenance. This is a novel role for this developmental protein in non-motile post-mitotic photoreceptor cells. Our preliminary results strongly indicate NUDC is involved in a molecular pathway that regulates and maintains the F-actin architecture necessary for disk structure, including the proteins cofilin1 and heat shock protein 90 (HSP90). Our data show NUDC regulates cofilin1 (CFL1) to maintain the F-actin architecture necessary for disk structure. Our preliminary data also show that NUDC affects mitochondria size and localization within the inner segment of rod cells, most likely due to NUDC’s regulation of the microtubule network in these cells. In addition, we have identified a novel role of NUDC as a neuroprotective agent in retinal degenerations, most likely through the inhibition of HSP90.