Retinitis pigmentosa: rapid neurodegeneration is governed by slow cell death mechanisms |
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| Authors: | A Sahaboglu O Paquet-Durand J Dietter K Dengler S Bernhard-Kurz P AR Ekstr?m B Hitzmann M Ueffing F Paquet-Durand |
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| Institution: | 1Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany;2Institute of Food Science and Biotechnology, University of Stuttgart Hohenheim, Stuttgart, Germany;3Skin Clinic, University of Tübingen, Tübingen, Germany;4Department of Clinical Sciences, Lund, University of Lund, Lund, Sweden |
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| 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. |
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| Keywords: | TUNEL apoptosis necrosis retina cGMP |
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