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.

Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa

“…It has been recently suggested that dying photoreceptors in retinitis pigmentosa display features and kinetics that differ from those of classical apoptosis and necrosis and that may constitute a new type of cell death. 56 In some…”

Inhibition of Mitochondrial Pyruvate Transport by Zaprinast Causes Massive Accumulation of Aspartate at the Expense of Glutamate in the Retina

“…Interestingly, in long term organotypic retinal explant cultures, at concentrations of up to 200 M, Zaprinast induces selective photoreceptor death without affecting other retinal neurons (37). Why does Zaprinast not cause generalized cell death and instead appears to affect only PDE6 under culture conditions (37)(38)(39)(40)? Tissue culture medium, such as R16 (41), used for organotypic retinal culture contains both fatty acids and glutamine.…”

Mathematical models of retinitis pigmentosa: The oxygen toxicity hypothesis

“…High oxygen levels are toxic to photoreceptors, since they result in an excess of reactive oxygen species, which cause damage to lipids, proteins and DNA (Shen et al, 2005). Studies using human epithelial cells (Wang et al, 2003) and rd1 mouse photoreceptors (Sahaboglu et al, 2013) show that cells take about 72 hours to die from hyperoxia. This corresponds to a timescale of decades for degeneration to spread across the retina (given that approximately 4000 photoreceptors lie along any direct path traced through the retina between the ora serrata and the fovea and assuming sequential cell death), a timescale consistent with degeneration in humans (Hartong et al, 2006).…”