In the visual system, the activation of rhodopsin by a photon of light initiates a chain of events referred to as the photo transduction cascade. The inactivation of this cascade is achieved at one level by the binding of the regulatory protein arrestin to rhodopsin. A mechanism of photoreceptor cell degeneration has previously been described in Drosophila where the normally transient interaction between rhodopsin and arrestin is stabilized. These rhodopsin/arrestin complexes are internalized into the cell body of the photoreceptor cell resulting in the loss of nearly all rhodopsin from the rhabdomeric membrane. The rhodopsin is not degraded but instead accumulates in the late endosome as insoluble aggregates, eventually leading to photoreceptor cell death. Recently we have determined that the NF-kB homologues Relish Dorsal and two different innate immunity pathways are necessary for this form of photoreceptor cell degeneration. The innate immunity pathway is a highly conserved signaling pathway that protects cells from gram-negative bacterial infection. In addition to immunity signaling, NF-kB is a well-studied transcription factor that is also involved n cell proliferation, inflammation, and cell protection. Since NF-kB functions as an antiapoptotic molecule, the cell death inducing function found in the Drosophila retina is novel. In this grant, we propose to further investigate the role of NF-kB in endocytosis-mediated cell death. This will be accomplished by a genetic screen aimed at isolating suppressors of retinal degeneration. A subset of the suppressors will be selected for future study. This work is the first description of NF-kB signaling being utilized in retinal degeneration.
The proposed research uses the fruit fly Drosophila melanogaster to study the molecular mechanism of retinal degeneration. Drosophila is a valuable model system to study retinal degeneration, since mutations in specific proteins that cause retinal disease in humans also affects the integrity of the fly eye. We will use genetic and molecular methods to dissect a novel pathway that leads to cell death and degeneration in the Drosophila retina.
