title: How long does a photoreceptor cell take to die? Implications for the causative cell death mechanisms.
abstract: The duration of cell death may allow deducing the underlying degenerative mechanism. To find out how long a photoreceptor takes to die, we used the rd1 mouse model for retinal neurodegeneration, which is characterized by phosphodiesterase-6 (PDE6) dysfunction and photoreceptor death triggered by high cGMP levels. Based on cellular data on the progression of cGMP accumulation, cell death, and survival, we created a mathematical model to simulate the temporal development of the degeneration and the clearance of dead cells. Both cellular data and modelling suggested that at the level of the individual cell, the degenerative process was rather slow, taking around 80 h to complete. Organotypic retinal explant cultures derived from wild-type animals and exposed to the selective PDE6 inhibitor zaprinast, confirmed the surprisingly long duration of an individual photoreceptor cell's death. We briefly discuss the possibility to link different cell death stages and their temporal progression to specific enzymatic activities known to be causally connected to cell death. This in turn opens up new perspectives for the treatment of inherited retinal degeneration, both in terms of therapeutic targets and temporal windows-of-opportunity.
authors.affiliation: François Paquet-Durand, Institute for Ophthalmic Research, University of Tübingen, Röntgenweg 11, 72076, Tübingen, Germany, francois.paquet-durand@klinikum.uni-tuebingen.de.
authors.forename: F
authors.initials: F
authors.lastname: Paquet-Durand
authors.forename: A
authors.initials: A
authors.lastname: Sahaboglu
authors.forename: J
authors.initials: J
authors.lastname: Dietter
authors.forename: O
authors.initials: O
authors.lastname: Paquet-Durand
authors.forename: B
authors.initials: B
authors.lastname: Hitzmann
authors.forename: M
authors.initials: M
authors.lastname: Ueffing
authors.forename: P A R
authors.initials: PA
authors.lastname: Ekström
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism; D004195:Disease Models, Animal; D006655:Histone Deacetylases / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009336:Necrosis / Q000378:metabolism; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology*
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D017869:Cyclic GMP-Dependent Protein Kinases; D006655:Histone Deacetylases; D006152:Cyclic GMP