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Ayse Sahaboglu, Melanie Barth, Manoj Kulkarni, Francois Paquet-Durand; PARP inhibition: Could a target for cancer therapy also be a target for the treatment of Retinitis Pigmentosa? . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5461.
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© ARVO (1962-2015); The Authors (2016-present)
Poly-ADP-ribosylation (PARylation) is one of the most important post-translational modifications of histone proteins. As such it is involved in many cellular pathways including transcription, DNA repair, and cell death. PARylation is performed by the enzyme poly-ADP-ribose-polymerase (PARP) using NAD+ and antagonized by poly-ADP-ribose-glycohydrolase (PARG) which hydrolyses PAR polymers from acceptor proteins. Currently, several PARP inhibitors are tested clinically for the treatment of different types of cancer. However, excessive PARP activity is also known to be involved in photoreceptor degeneration in various animal models for Retinitis Pigmentosa. Therefore, we investigated the therapeutic potential of clinically used PARP inhibitors on inherited photoreceptor degeneration using in vitro organotypic explant cultures derived from rd1, rd2, and rd10 mice.
rd1, rd2, rd10, and corresponding wild-type (wt) retinae were analyzed at the peak of degeneration using TUNEL staining for the detection of cell death, PARP in situ activity assay, and PAR immunohistochemistry. Retinal explants derived from wild-type, rd1, rd2,and rd10 animals were cultured under serum free conditions with/without different concentrations of PARP inhibitors PJ34, (A-99) and (R-99).
The TUNEL assay and PAR accumulation showed a significant increase in photoreceptor layers in rd1, rd2, rd10. Retinal explants treated with PARP inhibitors (A-99; R-99) showed a significant decrease in the number of dying cells and in the number of cells showing PAR accumulation, when compared to their untreated counterparts.
Three different animal models for Retinitis Pigmentosa, carrying different mutations all showed an increase in PARP activity and PAR accumulation concomitant with photoreceptor degeneration. The inhibition of PARP protected rd1, rd2, rd10 photoreceptors from mutation-induced cell death suggesting a high therapeutic potential for neuroprotective strategies aimed at inhibiting PARP. The fact that several PARP inhibitors are already in clinical use for the treatment of cancer should facilitate a translation into a treatment for Retinitis Pigmentosa and related inherited diseases of the retina.
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