RD3: A Challenge and a Promise - Abstract
Photoreceptor cells are highly specialized cells that convert light energy into electric signals. Ten percent of their outer segment membranes (approximately 77 cm2 of membrane) are renewed every day. Therefore, photoreceptor cells must possess an extraordinary trafficking system to provide material needed to build up outer segment discs through a 0.3 µm diameter connecting cilium. The mechanism to traffic membrane proteins in the retina and corresponding degenerative diseases is still elusive. The retinal degeneration 3 (Rd3) is the gene responsible for a murine autosomal recessive hereditary retinal degeneration, which is known as Leber Congenital Amaurosis 12 (LCA12). Degeneration of photoreceptor cells begins at about two weeks of age and completes between two and four months. We generated the first antibody against RD3, and through a protein-protein interaction analysis, discovered that the RD3 protein interacts directly with guanylate cyclase 1 (GC1), and partially expresses in the outer segment. We also detected the major binding site between these two proteins and realized that RD3 is directly involved in the trafficking of this crucial protein. In a separate study; we reported that RD3 negatively regulates GC1, which is crucial for efficient trafficking of GC1. During the trafficking path, RD3 prevents unnecessary production of cGMP. It is possible that RD3 may still be involved in regulating GC1 even after targeting. Several mutations that cause visual difficulties have been reported for the mouse and human ortholog of RD3. The symptoms these mutations cause are very similar to those reported for a more severe form of blindness referred to as LCA1. Therefore, RD3 might cause a broader range of retinal diseases. Gene replacement of RD3 has been shown to restore the GC1 across the retina. This makes RD3 a novel therapeutic target for retinal targeting of impaired degenerative
diseases.