Novel Locus Required For Photoreceptor Survival

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DESCRIPTION (provided by applicant): Genetic defects that lead to photoreceptor cell death in age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are highly heterogeneous and now include a list of more than 132 genes. Using Drosophila as a molecular genetic model for unraveling genetic loci in retinal degeneration disorders, such as AMD and RP, we have recently identified an entirely new class of molecules that are critical to photoreceptor viability and cell function. This is a class of sodium dependent symporters or co-transporters that move small molecules across membranes in exchange for sodium. Photoreceptors in Drosophila and humans alike possess several transport systems such as the sodium/calcium (-potassium) exchangers (NCKX) and the ABC transporters. Based on these and other similarities between Drosophila and human visual systems, we propose that the sodium dependent transporters may be critical loci in certain genetically inherited forms of human retinal degeneration. Mutations in the sodium dependent co-transporter lead to photoreceptor pathology and age-related retinal degeneration in Drosophila. In addition, these mutations also cause defects in the molecular weight of rhodopsin. We propose a link between the sodium dependent co-transporter and rhodopsin. In many cases, sodium dependent co-transporters are critical in protecting cells against oxidative damage. Oxidative damage is thought to contribute to AMD and RP as well as diabetic retinopathy. Therefore, sodium dependent transporters may be important loci in some forms of retinal degeneration. Unmasking novel classes of molecules opens up whole new areas of research as well as the development of new therapeutic strategies. Our data continue to support the concept that studies in Drosophila are highly valuable for uncovering the basis of retinal degeneration in humans. Drosophila offers quick insight into new classes of proteins that are strong candidates for photoreceptor function and retinal disease. The high impact and innovation in this application is to utilize the power of Drosophila molecular genetics to provide needed insights into novel loci and mechanisms in retinal degeneration disease. This study provides a rapid translation between Drosophila and humans through collaboration between Drosophila and human genetics laboratories.