Characterization of rhodopsin mis-sorting and constitutive activation in atransgenic rat model of retinitis pigmentosa

PURPOSE. To determine the extent to which rhodopsin mis-sorting and constit utive activation of the phototransduction cascade contribute to retinal deg eneration In a transgenic rat model of retinitis pigmentosa. METHODS. Retinas from transgenic rats expressing truncated rhodopsin (Ser33 4ter) were examined by light and electron microscopic immunocytochemistry a t several time points. Retinal degeneration in transgenic rats raised in da rkness was evaluated by quantification of outer nuclear layer thickness and by electroretinography. RESULTS. Mutant rhodopsin was found at inappropriately high levels in the p lasma membrane and cytoplasm of Ser334ter rat photoreceptors. When the cell death rate was high this mis-sorting was severe, but mis-sorting attenuate d greatly at later stages of degeneration, as the cell death rate decreased . The distributions of two other outer segment proteins (the cGMP-gated cha nnel and peripherin) were examined and found to be sorted normally within t he photoreceptors of these rats. Raising Ser334ter transgenic rats in darkn ess resulted in minimal rescue from retinal degeneration. CONCLUSIONS. Because dark rearing Ser334ter rats results in little rescue, it is concluded that constitutive activation of the phototransduction casca de does not contribute significantly to photoreceptor cell death in this ra t model. The nature of the rhodopsin sorting defect and the correlation bet ween the severity of mis-sorting and rate of cell death indicate that trunc ated rhodopsin map cause apoptosis by interfering with normal cellular mach inery in the post-Golgi transport pathway or in the plasma membrane.