Abstract
Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases affecting photoreceptors and causing blindness in humans. Previously, excessive activation of enzymes belonging to the poly-ADP-ribose polymerase (PARP) group was shown to be involved in photoreceptor degeneration in the human homologous rd1 mouse model for RP. Since there are at least 16 different PARP isoforms, we investigated the exact relevance of the predominant isoform - PARP1 - for photoreceptor cell death using PARP1 knock-out (KO) mice. In vivo and ex vivo morphological analysis using optic coherence tomography (OCT) and conventional histology revealed no major alterations of retinal phenotype when compared to wild-type (wt). Likewise, retinal function as assessed by electroretinography (ERG) was normal in PARP1 KO animals. We then used retinal explant cultures derived from wt, rd1, and PARP1 KO animals to test their susceptibility to chemically induced photoreceptor degeneration. Since photoreceptor degeneration in the rd1 retina is triggered by a loss-of-function in phosphodiesterase-6 (PDE6), we used selective PDE6 inhibition to emulate the rd1 situation on non-rd1 genotypes. While wt retina subjected to PDE6 inhibition showed massive photoreceptor degeneration comparable to rd1 retina, in the PARP1 KO situation, cell death was robustly reduced. Together, these findings demonstrate that PARP1 activity is in principle dispensable for normal retinal function, but is of major importance for photoreceptor degeneration under pathological conditions. Moreover, our results suggest that PARP dependent cell death or PARthanatos may play a major role in retinal degeneration and highlight the possibility to use specific PARP inhibitors for the treatment of RP.
Highlights
Blindness is a devastating condition that severely affects the quality of human life
Both rod and cone photoreceptor signalling appeared to be normal in PARP1 KO, since neither type of measurement revealed any signs of impaired retinal function
Zaprinast treatment resulted in a 200% elevation of cell death in wt retina, compared to only 17% increase in PARP1 KO (Fig. 3P). These results suggest that the photoreceptor cell death that follows upon phosphodiesterase 6 (PDE6) inhibition and subsequent accumulation of cGMP, to a major extent is dependent on PARP1 activity, since PARP1 KO displayed strong resistance to this paradigm of induced photoreceptor degeneration
Summary
Blindness is a devastating condition that severely affects the quality of human life. Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases that result in selective cell death of photoreceptors and is regarded as the main cause of blindness among the working age population in the developed world [1]. The retinal degeneration 1 (rd or rd) human homologous mouse model for RP is characterized by a loss-of-function mutation in the gene encoding for the b-subunit of rod photoreceptor cGMP phosphodiesterase 6 (PDE6) [3]. Non-functional PDE6 leads to accumulation of cGMP which occupies a key role in the vertebrate phototransduction cascade; excessively high cGMP levels trigger photoreceptor degeneration [5,6]. The rd mouse is one of the most studied animal models for RP and previously we demonstrated an involvement of excessive poly (ADP-ribose) polymerase (PARP) activity in rd photoreceptor cell death [7]
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