Apoptotic photoreceptor cell death in mouse models of retinitis pigmentosa.

TLDR

Retinitis pigmentosa is an inherited disease characterized by progressive photoreceptor degeneration that leads to visual loss, but it is unclear whether the underlying cell death is necrotic or apoptotic. The study tests whether photoreceptor death in three RP mouse models—rds, rd, and rhodopsin Q344ter—occurs via an apoptotic mechanism. Apoptosis was assessed using agarose gel electrophoresis for internucleosomal DNA fragmentation and in situ TUNEL labeling of apoptotic cells. Both assays revealed extensive photoreceptor apoptosis in all three models, and similar apoptotic events were observed during normal retinal development, indicating that targeting apoptosis could slow retinal degeneration.

Abstract

Retinitis pigmentosa (RP) is a group of inherited human diseases in which photoreceptor degeneration leads to visual loss and eventually to blindness. Although mutations in the rhodopsin, peripherin, and cGMP phosphodiesterase genes have been identified in some forms of RP, it remains to be determined whether these mutations lead to photoreceptor cell death through necrotic or apoptotic mechanisms. In this paper, we report a test of the hypothesis that photoreceptor cell death occurs by an apoptotic mechanism in three mouse models of RP: retinal degeneration slow (rds) caused by a peripherin mutation, retinal degeneration (rd) caused by a defect in cGMP phosphodiesterase, and transgenic mice carrying a rhodopsin Q344ter mutation responsible for autosomal dominant RP. Two complementary techniques were used to detect apoptosis-specific internucleosomal DNA fragmentation: agarose gel electrophoresis and in situ labeling of apoptotic cells by terminal dUTP nick end labeling. Both methods showed extensive apoptosis of photoreceptors in all three mouse models of retinal degeneration. We also show that apoptotic death occurs in the retina during normal development, suggesting that different mechanisms can cause photoreceptor death by activating an intrinsic death program in these cells. These findings raise the possibility that retinal degenerations may be slowed by interfering with the apoptotic mechanism itself.