Knockout of PARG110 confers resistance to cGMP-induced toxicity in mammalian photoreceptors.
Hereditary retinal degeneration (RD) relates to a heterogeneous group of blinding human diseases in which the light sensitive neurons of the retina, the photoreceptors, die. RD is currently untreatable and the underlying cellular mechanisms remain poorly understood. However, the activity of the enzyme poly-ADP-ribose polymerase-1 (PARP1) and excessive generation of poly-ADP-ribose (PAR) polymers in photoreceptor nuclei have been shown to be causally involved in RD. The activity of PARP1 is to a large extent governed by its functional antagonist, poly-ADP-glycohydrolase (PARG), which thus also may have a role in RD. To investigate this, we analyzed PARG expression in the retina of wild-type (wt) mice and in the rd1 mouse model for human RD, and detected increased PARG protein in a subset of degenerating rd1 photoreceptors. Knockout (KO) animals lacking the 110 kDa nuclear PARG isoform were furthermore analyzed, and their retinal morphology and function were indistinguishable from wild-type animals. Organotypic wt retinal explants can be experimentally treated to induce rd1-like photoreceptor death, but PARG110 KO retinal explants were unexpectedly highly resistant to such treatment. The resistance was associated with decreased PAR accumulation and low PARP activity, indicating that PARG110 may positively regulate PARP1, an event that therefore is absent in PARG110 KO tissue. Our study demonstrates a causal involvement of PARG110 in the process of photoreceptor degeneration. Contrasting its anticipated role as a functional antagonist, absence of PARG110 correlated with low PARP activity, suggesting that PARG110 and PARP1 act in a positive feedback loop, which is especially active under pathologic conditions. This in turn highlights both PARG110 and PARP1 as potential targets for neuroprotective treatments for RD.
Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tubingen, Germany.
A
A
Sahaboglu
Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Tuebingen, Germany.
N
N
Tanimoto
Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tubingen, Germany.
S
S
Bolz
Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Tuebingen, Germany.
M G
MG
Garrido
Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tubingen, Germany.
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M
Ueffing
Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Tuebingen, Germany.
M W
MW
Seeliger
Department of Otolaryngology, Tuebingen Hearing Research Centre, Tuebingen, Germany.
H
H
Löwenheim
Division of Ophthalmology, Department of Clinical Sciences, University of Lund, Lund, Sweden.
P
P
Ekström
Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Tubingen, Germany.
F
F
Paquet-Durand
D000818:Animals; D016923:Cell Death; D000242:Cyclic AMP / Q000378:metabolism*; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000037:antagonists & inhibitors / Q000235:genetics; D004195:Disease Models, Animal; D004789:Enzyme Activation; D020022:Genetic Predisposition to Disease; D006026:Glycoside Hydrolases / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D009410:Nerve Degeneration; D010641:Phenotype; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics; D020033:Protein Isoforms; D012162:Retinal Degeneration / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D046509:Tissue Culture Techniques
D010726:Phosphodiesterase Inhibitors; D020033:Protein Isoforms; D011064:Poly Adenosine Diphosphate Ribose; D000242:Cyclic AMP; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517438:Pde6b protein, mouse; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase