Retinal Degeneration in a Mouse Model of Retinitis Pigmentosa: Rpe65 as Modifier Gene and Role of Phototransduction, c–Fos, Caspase–1 and Prion Protein in the Degenerative Process

Abstract

Abstract: : Purpose: Photoreceptor degeneration in the VPP mouse, a model for human RP, is accelerated by light exposure. Several factors are known to influence light–induced retinal degeneration in wild–type mice. With the generation of double mutant mice, we tested the role of such factors in the VPP mouse. Methods: VPP mice have three mutations at the N–terminus of the gene encoding rod opsin. These mice were crossed with several transgenic and mutant mouse strains to create double mutant mice. Mice used included Rpe65_450Met, Rpe65_450Leu, Rpe65 knockout, Transducin knockout, c–fos knockout, Prion protein (PrP) overexpressing mice, PrP knockouts and Caspase–1 knockouts. Retinal degeneration was monitored by light–microscopy and rhodopsin quantification at 3, 4, 6 and 8 weeks of age. Results: Retinas of VPP mice on the Rpe65_450Leu background degenerated faster than those on the Rpe65_450Met background. Dark–rearing of VPP;Rpe65_450Leu mice attenuated the degeneration. Surprisingly, the Rpe65 knockout did only slow but not protect against degeneration. The degenerative process was not influenced by lack of c–Fos but was slowed by the lack of functional transducin. Overexpression of prion protein improved retinal morphology especially at early timepoints. Similarly, deletion of caspase–1 protease substantially delayed retinal degeneration in the VPP mouse. Conclusions: Rpe65 acts as a modifier gene for retinal degeneration induced by the VPP mutations. Through the modulation of rhodopsin regeneration kinetics, the Rpe65_450Leu variant may increase photon absorption capacity by rhodopsin leading to enhanced apoptotic photoreceptor loss. Retinal degeneration in VPP mice may involve phototransduction but may be independent of transcription factor AP–1/c–Fos. Thus, our data suggest that VPP follows – at least in part – the pathway of long–term, low–level light–induced degeneration. Caspase–1 is strongly induced during VPP–mediated degeneration and lack of Caspase–1 substantially delays degeneration suggesting an important role of this protease in the degenerative process. Finally, cellular prion protein may act as a neuroprotective agent in the retina.

Keywords: retinal degenerations: cell biology • neuroprotection • photoreceptors