Stephanie A. Hagstrom, Ph.D.

Cleveland Clinic - Visionary

Project Title: "The Role of Tulp1 in Photoreceptor Protein Trafficking"
 
Retinitis pigmentosa (RP) incorporates a large number of inherited retinal disorders characterized by photoreceptor degeneration.  RP is genetically and phenotypically heterogeneous, affecting over 1 million individuals worldwide. Mutations in a gene called TULP1 underlie an early-onset and severe form of autosomal recessive RP. Tulp1 is a protein exclusive to photoreceptor cells, and although the function of Tulp1 remains elusive, there is evidence from the murine model lacking Tulp1 that it plays a role in intracellular protein movement in multiple compartments of the photoreceptor.  In tulp1-/- mice, prior to photoreceptor degeneration, rod and cone opsins are mislocalized, and rhodopsin-bearing extracellular vesicles accumulate around the ellipsoid region of the inner segment (IS), indicating that Tulp1 is necessary for the transport of proteins to the outer segment (OS).  These mice also have a synaptic malformation that precedes photoreceptor degeneration and most likely interferes with the proper development of post-receptoral neurons. The absence of Tulp1 results in abnormalities that affect structure and function in multiple retinal sites, as well as causing distinct abnormalities in separate photoreceptor compartments.  This suggests that it either performs a general role throughout the photoreceptor or participates in multiple distinct pathways.  Based on our published work, the central hypothesis of this proposal is that Tulp1 is a component of the molecular machinery involved in the vesicular movement of proteins in the photoreceptor cell.

At the successful completion of this work, we will position Tulp1 in a functional context and define its mechanism of action. Our results will provide insight into the functional organization of photoreceptor protein transport pathways, as well as insight into the perturbation of retinal function associated with TULP1 mutations.  Finally, this project has potential for significantly impacting an important aspect of photoreceptor biology relevant to human retinal disease.