Purchase this article with an account.
F. Paquet-Durand, J. Sancho-Pelluz, A. Sahaboglu, P. Farinelli, S. Azadi, T. van Veen, J. Romero, P. Ekstrom; Interplay Between HDAC And PARP Activity During rd1 Mouse Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4088.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Retinitis Pigmentosa (RP) is one of the leading causes of blindness in the developed world and is at present untreatable. The underlying neurodegenerative mechanisms are unknown but may involve post-translational modifications of histones, known to affect cell death and survival. Such modifications may be introduced by histone acetyl transferases (HATs) and histone deacetylases (HDACs), which mediate acetylation and deacetylation, respectively, or by poly-ADP-ribose polymerase (PARP). The aim of this study was to investigate the interplay between histone acetylation, deacetylation and poly-ADP-ribosylation and to study their relevance for photoreceptor survival in the rd1 mouse model for RP.
Retinae were obtained from rd1 and wt animals either directly or after in vitro culture and treatment with inhibitors specific for HDACs. Protein acetylation and poly-ADP-ribosylation was studied using immunofluorescence and western blot. Cell death was assessed using TUNEL assay. In situ activity assays for HDACs and PARP were performed to study activity of different classes of these enzymes in rd1 and wt retinae.
We found acetylation of histones and other proteins to be dramatically reduced in degenerating photoreceptors in the rd1 mouse retina while poly-ADP-ribosylation was strongly increased. The activity assays for HDAC and PARP showed a positive reaction in rd1 photoreceptors, when compared with wt. Activation of HDAC class I/II temporally preceded PARP activity and photoreceptor degeneration. Inhibition of HDAC class I/II reduced activation of PARP and increased rd1 photoreceptor survival in vitro.
HDACs are likely to be involved in the development and progression of photoreceptor cell death in the rd1 mouse and may directly or indirectly trigger activation of PARP. These findings highlight the importance of protein acetylation for photoreceptor cell death and survival and propose certain HDAC classes as novel targets for the pharmacological intervention in RP.
This PDF is available to Subscribers Only