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Marina S Gorbatyuk, Christopher Starr, Priyamvada M Pitale; Progressive Retinal Degeneration is Accompanied by Translational Inhibition in Mouse Retinas.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3048.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal photoreceptor cells are neurons with a great demand for continuous protein synthesis. Formation of the initiation complex is a major event of translational control regulated by multiple eukaryotic initiator factors (eIF), an upstream effector mTOR kinase and a translational inhibitor, eIF4E-BP1. A recent study demonstrated that mutations within gene encoding TRNT1 critical for tRNA processing cause a retinitis pigmentosa likely associated with reduced protein synthesis. Therefore, our goal was to verify whether varied retinal degenerations (RD) progresses with translational attenuation and altered activities of eIF2α, mTOR and eIF4E-BP1.
Retinal protein extracts were isolated from rd16, rd10 and T17M RHO mice to analyze phosphorylated (p) eIF2α, AKT, mTOR and eIF4E-BP1 at P15 and P20. The SUnSET method was applied to evaluate translational rates. To assess the role of PERK in translational control, we employed eIF2a kinase (PERK) inhibitor (i), GSK2606414. The compound was delivered to degenerating retinas by oral gavage at a dose of 50 mg/kg twice a day for two days.
We found translational rates dramatically attenuated in all RD models. Herewith, rd16, T17M RHO and rd10 mice demonstrated 43%,40% and 62% translational inhibition, respectively. In addition, translational attenuation was accompanied by an increase in p-eIF2α ranging from 8 to 90% and decrease in p-AKT and p-mTOR ranging from 28 to 57% and from 12 to 154%, respectively. The significant reduction in p-mTOR was in agreement with reduced levels of p-eIF4E-BP1 by 53% suggesting eIF4E-BP1 is able to better interact with eIF4E and form an inactive translation initiation complex in mice with retinal degeneration. In vivo inhibition of PERK significantly downregulated p-eIF2α; however, this resulted in only partial restoration of translational rate suggesting there are other controllers of protein synthesis in the retina during retinal degeneration.
For the first time, we demonstrate a link between RD and translational inhibition in the retina. However, whether translational inhibition could be a cause of progressive RD needs to be verified. Future experiments are needed to validate strategies aimed at augmenting p-AKT/p-mTOR/p-eiF4E-BP1 signaling to withdraw translational attenuation and restore protein synthesis in degenerating retinas.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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