Research Projects

Retinitis pigmentosa (RP) is a rare, inherited retinal disorder affecting over 1.5 million people globally. RP predominantly affects rod photoreceptors, which are critical for scotopic (low-light) vision, with night blindness serving as an early clinical manifestation. A key molecular component of rod photoreceptors is rhodopsin, a G-protein-coupled receptor essential for phototransduction. Mutations in the rhodopsin gene and associated accessory genes that regulate its folding and intracellular transport have been implicated as major contributors to RP pathogenesis. The rod outer segment contains densely packed membrane discs that maximize light absorption and house phototransduction components like rhodopsin. Despite their structural complexity, the mechanisms stabilizing these discs remain unclear. Photoreceptor cells average 100 µm in length, with discs ~10 nm thick and spaced ~25 nm apart. Rhodopsin's extracellular domains, including glycosylated N-terminal residues and loops, span ~20 nm, constituting two-thirds of the inter-disc spacing. The dense packing of rhodopsin molecules suggests close proximity of their extracellular domains, potentially facilitating head-to-head dimerization, a mechanism hypothesized to contribute to the structural stability of the outer segment. Our initial study underscores the critical role of the C-terminal tail in rhodopsin transport, although the underlying mechanism remains incompletely understood. Two prevailing models describe this process: one involving the formation of a ciliary target complex for rhodopsin transport mediated by G-protein Arf4 and the Arf-activating protein ASAP1 which interacts with rhodopsin and acts as a platform for the assembly of additional ciliary transport proteins which regulates rhodopsin trafficking. Another proposed model is direct transport by unconventional motor protein MOY1C, which binds rhodopsin’s C-terminal domain. To elucidate these mechanisms, this study proposes isolating and characterizing proteins that interact with the rhodopsin C-terminal tail. The C8orf37 protein was earlier shown to localize within the primary cilium, where it is essential for maintaining ciliary function. Deletion of the C8orf37 gene has been associated with Bardet-Biedl syndrome, retinitis pigmentosa, and cone-rod dystrophy. However, the mechanisms by which C8orf37 influences these pathological outcomes are unclear. Preliminary experiments involving the overexpression of C8orf37 in IMCD3 cells revealed an unexpected distribution pattern. Rather than localizing to the cilium, C8orf37 accumulated predominantly in the nucleus, suggesting a potential role in regulating the expression of photoreceptor-specific proteins. This study aims to elucidate the molecular mechanisms underpinning photoreceptor stability and function by addressing these objectives. These findings will contribute to a deeper understanding of RP pathogenesis and may identify novel therapeutic targets for intervention.