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A. Choi, F. Lamoke, L. Camit, X. Yang, P. A. Wood, W. J. M. Hrushesky, W. J. Jahng; Visual Cycle Controls Neuroprotection Switch in the Eye. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2949.
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Studies on the retinal degeneration seen in diseases such as Age-related Macular Degeneration (AMD) and glaucoma show apoptosis to be the primary mechanism of irregular cell death. Neuroprotective proteins such as erythropoietin (EPO), erythropoietin receptor (EPOR) and Bclx are known to have an anti-apoptotic effect in response to light triggers within the eye. The mechanisms to regulate the expression of proteins that protect against light-induced oxidative stress remain elusive. In this study, we characterize the interplay between the controls in the visual cycle and the resulting neuroprotection switch to suggest that the visual cycle is the trigger for gene expression of EPO, EPOR, and Bclx in the eye.
Crude extracts of RPE membrane proteins from bovine, mouse, zebrafish’s eye were prepared using a mild solution of 1%Triton X-100 in PBS. Proteins were exposed to oxidative stress (hydrogen peroxide) or caspases. After reaction period, proteins were separated on a one-dimensional or two-dimensional SDS-PAGE and analyzed by Western blot and mass spectrometry. B6.129S7-Per2tm1Brd/J (B6) mice were kept on a twelve hour light-dark cycle or in constant darkness, and whole eyes were harvested every four hours. Phosphorylation was detected by staining protocols and mass spectrometry analysis.
A correlation existed between the concentration of EPO, EPOR, and Bclx and the concentration of hydrogen peroxide or caspases. EPO and EPOR expression in light-exposed samples contained differing amounts in comparison to dark-exposed samples. Bclx fragments contained dissimilar amounts in the light and the dark time points.
Our results reveal that in a hypoxic environment such as light exposure, there is an upregulation of neuroprotection. Along with evidence of a change in RPE65 concentration at different time points, our results suggest that EPO, EPOR, and Bclx expression in the eye are controlled by the visual cycle. Since RPE65 is linked to the biosynthesis and flux of retinoid in the visual cycle, it is anticipated that neuroprotective signals are also regulated by an internal rhythmicity controlled by biochemical reactions of retinoid undergone in visual processing.
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