Protection of Rpe65-deficient mice identifies rhodopsin as a mediator of light-induced retinal degeneration

Light-induced apoptosis of photoreceptors represents an animal model for re tinal degeneration(1). Major human diseases that affect vision, such as age -related macular degeneration (AMD) and some forms of retinitis pigmentosa (RP), may be promoted by light(2-7). The receptor mediating light damage, h owever, has not yet been conclusively identified; candidate molecules inclu de prostaglandin synthase(8), cytochrome oxidase(9), rhodopsin(10), and ops ins of the cones and the retinal pigment epithelium(11) (PE). We exposed to bright light two groups of genetically altered mice that lack the visual p igment rhodopsin (Rpe65(-/-) and Rho(-/-)). The gene Rpe65 is specifically expressed in the PE and essential for the re-isomerization of all-trans ret inol in the visual cycle and thus for the regeneration of rhodopsin after b leaching(12). Rho(-/-) mice do not express the apoprotein opsin in photorec eptors, which, consequently, do not contain rhodopsin(13). We show that pho toreceptors lacking rhodopsin in these mice are completely protected agains t light-induced apoptosis. The transcription factor AP-1, a central element in the apoptotic response to light(14,15), is not activated in the absence of rhodopsin, indicating that rhodopsin is essential for the generation or transduction of the intracellular death signal induced by light.