Activation of caspase-3 in the retina of transgenic rats with the rhodopsin mutation S334ter during photoreceptor degeneration

The role of caspase-3 in photoreceptor degeneration was examined in a line of transgenic rats that carry a rhodopsin mutation S334ter. Photoreceptor d egeneration in these animals is rapid. It is detected as early as postnatal day (PD) 8, and by PD 20, only one of the original 12 rows of nuclei remai n in the outer nuclear layer. At PD 11 and 12, the number of photoreceptors dying per day reaches a peak of similar to 30% of the total photoreceptors in the retina. Coincident with this rapid degeneration is an increase in c aspase-3-like activity as assessed by the cleavage of a fluorescent substra te N-acetyl-Asp-Glu-Val-Asp-aminomethylcoumarin and an increase in activate d caspase-3 as determined by Western blot analysis for its 12 kDa subunit. Intraocular injection of an irreversible caspase-3 inhibitor N-benzyloxycar bonal-Asp(OMe)-Glu(OMe)-Val-Asp(Ome)-fluoro-methyketone partially protected photoreceptors from degeneration. These findings indicate that a caspase-3 -dependent mechanism is operative in photoreceptor death in the transgenic rats under investigation.