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J. P. Silva, F. Paquet-Durand, T. Talukdar, L. Johnson, S. Hauck, M. Ueffing, T. Van Veen, P. Ekström; Poly(ADP-Ribose) Polymerase (PARP) Inhibition Rescues Photoreceptors in the rd1 Mouse. Invest. Ophthalmol. Vis. Sci. 2007;48(13):623.
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© ARVO (1962-2015); The Authors (2016-present)
The rd1 mouse represents a model for Retinitis Pigmentosa suffering from an inherited mutation that leads to an early and rapid degeneration of the retinal photoreceptors. However, in contrast to many other examples of degenerative cell death, the rd1 photoreceptors die in a caspase-independent way. The nuclear protein poly(ADP-ribose) polymerase (PARP) is important for cellular DNA repair mechanisms, but recent findings reveal that PARP, when overactivated, could itself contribute to cell death. PARP may thus take part in caspase-independent apoptosis, such as in the rd1 retina. The present study used an in vitro retinal explant system to examine the influence of PARP on rd1 retinal degeneration by applying the PARP inhibitor PJ34.
Retinas were collected from rd1 mice at PN5 or PN7, cultured until PN11 (short-term) or PN28 (long-term), respectively, fixed and cryo-sectioned. Long-term specimens were stained with hematoxylin/eosin for assessment of histology. The amount of ongoing cell death in short-term retinas was studied by TUNEL staining, whereas effects on the PARP system were analysed by immunofluorescent staining for either PARP or its enzymatic product, poly(ADP-ribose).
Concomitantly with a reduction in poly(ADP-ribose) staining, PJ34 treated short-term cultures had a significantly lower number of dying photoreceptors compared with vehicle as revealed by TUNEL staining. PJ34 treatment of long term cultures significantly increased the number of rows of surviving photoreceptors at PN28.
PARP inhibition reduced both the production of poly(ADP-ribose) and the extent of photoreceptor cell death, indicating that the PARP enzyme plays a role in the rd1 mouse photoreceptor degeneration. Inhibition of PARP may be of value for the therapy of retinal degenerations.
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