PARP1 gene knock-out increases resistance to retinal degeneration without affecting retinal function.
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.
Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
Ayse
A
Sahaboglu
Naoyuki
N
Tanimoto
Jasvir
J
Kaur
Javier
J
Sancho-Pelluz
Gesine
G
Huber
Edda
E
Fahl
Blanca
B
Arango-Gonzalez
Eberhart
E
Zrenner
Per
P
Ekström
Hubert
H
Löwenheim
Mathias
M
Seeliger
François
F
Paquet-Durand
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004596:Electroretinography; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011688:Purinones / Q000494:pharmacology; D012160:Retina / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D012162:Retinal Degeneration / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D041623:Tomography, Optical Coherence
D010726:Phosphodiesterase Inhibitors; D011688:Purinones; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C011145:zaprinast; D006152:Cyclic GMP