RHODOPSIN ACCUMULATION AT ABNORMAL SITES IN RETINAS OF MICE WITH A HUMAN P23H RHODOPSIN TRANSGENE

Purpose. To investigate the mechanism by which photoreceptors degenera te in transgenic mice carrying a mutant human rhodopsin gene (P23H). M ethods. The temporal and spatial pattern of the retinal degeneration c aused by P23H rhodopsin was mapped using immunocytochemistry with rhod opsin-specific antibodies. The subcellular localizations of rhodopsin, transducin, and rod cGMP phosphodiesterase (PDE) were also determined , and rhodopsin localization was compared among P23H transgenic mice, rd mice, and Royal College of Surgeons (RCS) rats. Results. In transge nic mice that express P23H rhodopsin, photoreceptors are lost centrall y by postnatal day 10. As the retina degenerates, rhodopsin accumulate s in the outer nuclear layer and within the photoreceptor synaptic ter minals. The P23H transgenic retinas also show an accumulation of trans ducin and PDE within the outer plexiform layer. In contrast, other typ es of hereditary retinal degenerations studied show a similar pattern of rhodopsin accumulation in the outer nuclear layer but not in the ou ter plexiform layer of the retina. Conclusions. The pattern of degener ation in the P23H transgenic retina is consistent with a model in whic h the centrally located, first-born photoreceptors are the first to di e. In contrast to other animal models for hereditary retinal degenerat ion (rd, RCS), a novel feature of the P23H degeneration is an accumula tion of rhodopsin, transducin, and PDE within the outer plexiform laye r of the retina. One hypothesis to explain this observation is that P2 3H rhodopsin is routed intracellularly through a pathway not used by n ormal rhodopsin. Nonmutant forms of the peripheral transducing protein s normally associated with disk membrane, such as transducin and PDE, may accompany the aberrantly routed rhodopsin.