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Kangwei Jiao, Ayse Sahaboglu, Eberhart Zrenner, Marius Ueffing, Per A R Ekström, Francois Paquet-Durand; PARP inhibition preserves photoreceptors in different Pde6a mutant animal models for Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2016;57(12):164.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in PDE6A are known to cause Retinitis Pigmentosa (RP). Here, we used four different mouse models that carry Pde6a homozygous and compound heterozygous mutations, genotype-matched to cases of human PDE6A RP. Since the activity of poly (ADP-ribose) polymerase (PARP) was previously found to contribute to photoreceptor loss in Pde6b mutant animals, we tested for PARP activity and neuroprotective efficacy of PARP inhibition also in the different Pde6a mutants.
We first characterized the progression of retinal degeneration in four different Pde6a mutants, namely the V685M, D670G, R562W, and V685M*R562W mutants, using photoreceptor survival, TUNEL assay, PARP activity, and PAR accumulation as markers. We then used organotypic retinal explant cultures to treat Pde6a mutant retinas for varying durations (until post-natal day (P)15, P19, P24) with the PARP specific inhibitor PJ34.
The progression of photoreceptor degeneration in vivo was always correlated with excessive PARP activation and PAR accumulation. In short-term in vitro treatment until P15, retinal cultures from all four Pde6a mutants showed a significant decrease in TUNEL positive, dying photoreceptors, which corresponded to increased photoreceptor survival: V685M: +20.7%±4.3%, p>0.05; V685M*R562W: +21.8%±5.2%, p<0.05; R562W: +36.0%±5.1%, p<0.05; D670G: +19.6%±4.6%, p<0.05 (mean values ± standard error of the mean). When culture duration and PJ34 treatment was increased, only slow degenerating mutants, notably the D670G, showed significant photoreceptor rescue, while the rapidly degenerating V685M did not benefit from long-term treatment.
PARP and PAR accumulation play a major role in photoreceptor degeneration in different Pde6a mutants, highlighting PARP as a common target for neuroprotective interventions in PDE6A RP. Our study may help to define the window-of-opportunity for different PDE6A mutations in future clinical interventions.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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