Quantifying the metabolic contribution to photoreceptor death in retinitis pigmentosa via a mathematical model
Department of Ophthalmology; Gene Therapy Center; UMass Metabolic Network
Biology | Cellular and Molecular Physiology | Eye Diseases | Ophthalmology
Retinitis pigmentosa (RP) is a family of inherited retinal degenerative diseases that leads to blindness. In many cases the disease-causing allele encodes for a gene exclusively expressed in the night active rod photoreceptors. However, because rod death always leads to cone death affected individuals eventually lose their sight. Many theories have been proposed to explain the secondary loss of cones in RP; however, most fail to fully explain the different pathological transition stages seen in humans. Incorporating experimental data of rod and cone death kinetics from two mouse models of RP, we use a mathematical model to investigate the interplay and role of energy consumption and uptake of the photoreceptors as well as nutrient availability supplied through the retinal pigment epithelium (RPE) throughout the progression of RP. Our data driven mathematical model predicts that the system requires a total reduction of approximately 27-31% in nutrients available to result in the complete demise of all cones. Simulations utilizing retinal degeneration 1 (rd1) mouse cell count data in which cone death was delayed by altering cell metabolism in cones show that preventing a 1-2% decrease in nutrients available can permanently halt cone death even when 90% have already died. Our results also indicate that the ratio of energy consumption to uptake of cones, Dc, is mainly disrupted during the death wave of the rods with negligible changes thereafter and that the subsequent nutrient decrease is mainly responsible for the demise of the cones. The change in this ratio Dc highlights the compensation that the cones must undergo during rod death to meet the high metabolic demands of the entire photoreceptor population. Global sensitivity analysis confirms the results and suggests areas of focus for halting RP, even at later stages of the disease, through feasible therapeutic interventions.
DOI of Published Version
J Theor Biol. 2016 Nov 7;408:75-87. doi: 10.1016/j.jtbi.2016.08.001. Epub 2016 Aug 9. Link to article on publisher's site
Journal of theoretical biology
Camacho ET, Punzo C, Wirkus SA. (2016). Quantifying the metabolic contribution to photoreceptor death in retinitis pigmentosa via a mathematical model. UMass Metabolic Network Publications. https://doi.org/10.1016/j.jtbi.2016.08.001. Retrieved from https://escholarship.umassmed.edu/metnet_pubs/23