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 degeneration 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 remain in the outer nuclear layer. At PD 11 and 12, the number of photoreceptors dying per day reaches a peak of approximately 30% of the total photoreceptors in the retina. Coincident with this rapid degeneration is an increase in caspase-3-like activity as assessed by the cleavage of a fluorescent substrate N-acetyl-Asp-Glu-Val-Asp-aminomethylcoumarin and an increase in activated caspase-3 as determined by Western blot analysis for its 12 kDa subunit. Intraocular injection of an irreversible caspase-3 inhibitor N-benzyloxycarbonal-Asp(OMe)-Glu(OMe)-Val-Asp(Ome)-fluoromethyk etone 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.
Liu
C
C
Department of Ophthalmology, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Li
Y
Y
Peng
M
M
Laties
A M
AM
Wen
R
R
D000818:Animals; D030801:Animals, Genetically Modified; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D003374:Coumarins / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006579:Heterozygote; D009154:Mutation / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D020419:Photoreceptor Cells, Vertebrate / Q000737:chemistry / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012162:Retinal Degeneration / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D012243:Rhodopsin / Q000235:genetics*; D019076:Transgenes / Q000502:physiology
C112287:Ac-aspartyl-glutamyl-valyl-aspartyl-aminomethylcoumarin; D061945:Caspase Inhibitors; D003374:Coumarins; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C096022:acetyl-tyrosyl-valyl-alanyl-aspartyl-7-amino-4-methylcoumarinamide; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D012243:Rhodopsin; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases