RT Journal Article
SR Electronic
T1 Excessive Activation of Poly(ADP-Ribose) Polymerase Contributes to Inherited Photoreceptor Degeneration in the Retinal Degeneration 1 Mouse
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 10311
OP 10319
DO 10.1523/JNEUROSCI.1514-07.2007
VO 27
IS 38
A1 François Paquet-Durand
A1 José Silva
A1 Tanuja Talukdar
A1 Leif E. Johnson
A1 Seifollah Azadi
A1 Theo van Veen
A1 Marius Ueffing
A1 Stefanie M. Hauck
A1 Per A. R. Ekström
YR 2007
UL http://www.jneurosci.org/content/27/38/10311.abstract
AB Retinitis pigmentosa (RP) is an inherited blinding disease for which there is no treatment available. It is characterized by a progressive and neurodegenerative loss of photoreceptors but the underlying mechanisms are poorly understood. Excessive activation of the enzyme poly(ADP-ribose) polymerase (PARP) has recently been shown to be involved in several neuropathologies. To investigate the possible role of PARP in retinal photoreceptor degeneration, we used the retinal degeneration 1 (rd1) mouse RP model to study PARP expression, PARP activity, and to test the effects of PARP inhibition on photoreceptor viability. PARP expression was found to be equal between rd1 and wild-type counterpart retinas. In contrast to this, a dramatic increase in both PARP activity per se and PARP product formation was detected by in situ assays in rd1 photoreceptors actively undergoing cell death. Furthermore, PARP activity colabeled with oxidatively damaged DNA and nuclear translocation of AIF (apoptosis-inducing factor), suggesting activation of PARP as a bridge between these events in the degenerating photoreceptors. The PARP-specific inhibitor PJ34 [N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide·HCl[ reduced the number of cells exhibiting death markers in a short-term retinal culture paradigm, a protective effect that was translated into an increased number of surviving photoreceptors when the inhibitor was used in a long-term culture setting. Our results thus demonstrate an involvement of PARP activity in rd1 photoreceptor cell death, which could have a bearing on the understanding of neurodegenerations as such. The findings also suggest that the therapeutical possibilities of PARP inhibition should include retinal diseases like RP.