Abstract
Retinitis pigmentosa (RP) is a heterogeneous group of inherited neurodegenerative diseases affecting photoreceptors and causing blindness. Many human cases are caused by mutations in the rhodopsin gene. An important question regarding RP pathology is whether different genetic defects trigger the same or different cell death mechanisms. To answer this question, we analysed photoreceptor degeneration in P23H and S334ter transgenic rats carrying rhodopsin mutations that affect protein folding and sorting respectively. We found strong activation of calpain and poly(ADP-ribose) polymerase (PARP) in both mutants, concomitant with calpastatin down-regulation, increased oxidative DNA damage and accumulation of PAR polymers. These parameters were strictly correlated with the temporal progression of photoreceptor degeneration, mirroring earlier findings in the phosphodiesterase-6 mutant rd1 mouse, and suggesting execution of non-apoptotic cell death mechanisms. Interestingly, activation of caspases-3 and -9 and cytochrome c leakage—key events in apoptotic cell death—were observed only in the S334ter mutant, which also showed increased expression of PARP-1. The identification of the same metabolic markers triggered by different mutations in two different species suggests the existence of common cell death mechanisms, which is a major consideration for any mutation independent treatment.
Highlights
Retinitis Pigmentosa (RP) is a genetically and clinically heterogeneous group of neurodegenerative diseases
General Morphology – transferase dUTP nick end labeling (TUNEL) staining Analysis of P23H and S334ter retinal cross-sections during the first postnatal (PN) month showed a progressive reduction in outer nuclear layer (ONL) thickness compared to CD rats as described previously [10,13]
In S334ter animals, a significant elevation of photoreceptor cell death was evident already at PN10, while the highest percentage of TUNELpositive ONL cells was found at PN12 (S334ter: 6.1%61.1 SD, n = 3; CD: 0.02%60.01 SD, n = 3, P,0.001) (Fig. 1B)
Summary
Retinitis Pigmentosa (RP) is a genetically and clinically heterogeneous group of neurodegenerative diseases. Symptoms of RP include night blindness, gradual loss of peripheral visual field and eventual loss of central vision, caused by initial death of rods and by secondary degeneration of cones, respectively [1]. The disease prevalence is about 1/4000 [2] with autosomal dominant (ADRP; 30–40%), autosomal recessive (56–60%) or X-linked (5– 15%) inheritance patterns [3]. Of particular importance are RP-causing mutations in the rhodopsin molecule. More than 100 different mutations have been documented in the rhodopsin gene, accounting for 30– 40% of ADRP cases and highly variable disease phenotypes depending on the location of the mutation [5]. The high prevalence and heterogeneity of rhodopsin mutations make it interesting to study the corresponding neurodegenerative mechanisms, not the least for the development of therapies
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