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Francois Paquet-Durand, Ayse Sahaboglu-Tekgöz, Olivier Paquet-Durand, Johannes Dietter, Per Ekstrom, Bernd Hitzmann, Marius Ueffing; How long does a photoreceptor take to die? Temporal characteristics of neuronal cell death in the retina. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5950.
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© ARVO (1962-2015); The Authors (2016-present)
The question as to how long a neuron takes to die, from beginning to end, remains unanswered for most neurodegenerative diseases. To address this question in a retina specific context, 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.
Using cellular data on the progression of cGMP accumulation, photoreceptor cell death, and survival, we created a mathematical model to simulate the temporal development of the degeneration and the clearance of dead cells. Organotypic retinal explant cultures were used to validate the predictions of the model.
Both cellular data and modelling suggested that at the level of the individual cell, the degenerative process was rather slow taking approximately 80h to complete. To test the predictions of the model, we employed organotypic retinal explant cultures derived from wild-type animals and exposed to the selective PDE6 inhibitor zaprinast. Interestingly, here, detectable cGMP accumulation occurred only 36h after the beginning of PDE6 inhibition, suggesting the activity of compensatory feedback mechanisms. A measurable increase in cell death occurred only another 36h later.
Our study allows discriminating three major stages in neuronal cell death: 1) an initiation phase between 36 to 40h, 2) the execution phase lasting another 36 to 40h, and finally 3) the clearance phase lasting about 7h. This work also highlights the paradox that photoreceptor neurodegeneration, while very rapid at the tissue level, is governed by cell death mechanisms that are surprisingly slow, much slower than what would be expected, for instance, from apoptotic cell death.
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