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A. Sahaboglu Tekgoz, T. Van Veen, F. Paquet-Durand; The Roles of Parp and Parg in Inherited Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4495.
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Inherited retinal degenerations such as Retinitis Pigmetosa (RP) are initiated by gene defects in rods, cones or the retinal pigment epithelium (RPE) and often lead to an irreversible loss in visual function. The retinal degeneration (rd) 1 mouse is a well studied model for RP in which the gene encoding for the beta subunit of the rod photoreceptor cGMP phosphodisterase 6 (PDE6) is mutated and consequently non-functional. PDE6 dysfunction causes accumulation of cGMP which has been shown to be associated with excessive poly (ADP-ribose) polymerase (PARP) activation and oxidative stress in the rd1 mouse. The aim of this study was to further investigate the roles of PARP and its antagonist poly-ADP-glycohydrolase (PARG) in retinal degeneration.
PARP knockout (KO), PARG KO and wild-type (wt) mouse retinal explants were cultured with/without Zaprinast, a selective inhibitor of cyclic GMP-specific phosphodiesterase, to simulate in vitro a situation comparable to the rd1 mouse model. Immunofluorescent detection of cGMP was used to confirm Zaprinast effects. TUNEL and Avidin staining were performed for analysis of dying cells and oxidative DNA damage respectively.
Immunofluorescence showed that in all groups (wt, PARP KO, PARG KO) zaprinast treatment induced an accumulation of cGMP in the outer nuclear layer. Detection of degenerating cells using the TUNEL assay showed a treatment induced increase in the number of positive cells in the outer nuclear layer of wt and PARP KO retinae. However, in PARG KO retinae no TUNEL positive cells were observed in the outer nuclear layer after zaprinast treatment. Similar results were obtained when the Avidin assay was used for detection of oxidative DNA damage.
The activities of PARP and PARG may be linked to the occurrence of oxidative DNA damage. Hence, PARP and PARG may have important functions in the retinal photoreceptor cell death in the rd1 mouse and could be new targets for therapeutic developments. Moreover, an understanding of the roles of PARP and PARG in retinal degenerations could shed new light on the existence or absence of alternative pathways for degradation of poly-ADP-ribose-polymers.
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