title: Retinitis pigmentosa: rapid neurodegeneration is governed by slow cell death mechanisms.
abstract: For most neurodegenerative diseases the precise duration of an individual cell's death is unknown, which is an obstacle when counteractive measures are being considered. To address this, we used the rd1 mouse model for retinal neurodegeneration, characterized by phosphodiesterase-6 (PDE6) dysfunction and photoreceptor death triggered by high cyclic guanosine-mono-phosphate (cGMP) levels. Using cellular data on cGMP accumulation, cell death, and survival, we created mathematical models to simulate the temporal development of the degeneration. We validated model predictions using organotypic retinal explant cultures derived from wild-type animals and exposed to the selective PDE6 inhibitor zaprinast. Together, photoreceptor data and modeling for the first time delineated three major cell death phases in a complex neuronal tissue: (1) initiation, taking up to 36 h, (2) execution, lasting another 40 h, and finally (3) clearance, lasting about 7 h. Surprisingly, photoreceptor neurodegeneration was noticeably slower than necrosis or apoptosis, suggesting a different mechanism of death for these neurons.
authors: Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
authors: A
authors: A
authors: Sahaboglu
authors: O
authors: O
authors: Paquet-Durand
authors: J
authors: J
authors: Dietter
authors: K
authors: K
authors: Dengler
authors: S
authors: S
authors: Bernhard-Kurz
authors: P Ar
authors: PA
authors: Ekström
authors: B
authors: B
authors: Hitzmann
authors: M
authors: M
authors: Ueffing
authors: F
authors: F
authors: Paquet-Durand
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011688:Purinones / Q000494:pharmacology*; D012160:Retina / Q000166:cytology / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000378:metabolism / Q000473:pathology
chemical_list: D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C011145:zaprinast; D006152:Cyclic GMP
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