Excessive activation of poly(ADP-ribose) polymerase contributes to inherited photoreceptor degeneration in the retinal degeneration 1 mouse.
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 x 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.
Paquet-Durand
François
F
Department of Ophthalmology, Lund University, 22185 Lund, Sweden. francois.paquet-durand@med.lu.se
Silva
José
J
Talukdar
Tanuja
T
Johnson
Leif E
LE
Azadi
Seifollah
S
van Veen
Theo
T
Ueffing
Marius
M
Hauck
Stefanie M
SM
Ekström
Per A R
PA
D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D020419:Photoreceptor Cells, Vertebrate / Q000201:enzymology* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012162:Retinal Degeneration / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
D011065:Poly(ADP-ribose) Polymerases