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.