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M. K. Ertel, K. G. Sheets, Y. Zhou, C.-C. Chan, J. Tuo, W. C. Gordon, N. G. Bazan; Endoplasmic Reticulum Stress Precedes Photoreceptor Degeneration in Ccl2-/-/Cx2cr1-/- Mice. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4031.
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The endoplasmic reticulum (ER) is a sensor of homeostatic disruptions that provides quality control to prevent unfolded or misfolded protein transit to the Golgi, channeling them to degradation. Retinal degenerations and other perturbations that accumulate misfolded proteins in the ER lumen trigger ER stress, which is expressed as the unfolded protein response in an attempt to cope with this abnormal buildup. In retinal degenerative diseases, ER stress markers are up-regulated. Consequently, in this study, we examined whether ER stress markers demonstrated increased expression in the Ccl2-/-/Cx3cr1-/- (DKO) mouse model of age-related macular degeneration (AMD).
Eyes from 2 and 18 month DKO mice and age matched C57/Bl6 controls were fixed, cryo-sectioned at 20 micron thickness, and immunohistochemically examined for ER stress markers (e.g., GRP78-BiP). Typical immunolocalization methods were employed. Confocal microscopy was used to visualize the location of this marker in histological sections.
Retinal sections from 18 month DKO mice, immunolabeled, demonstrated localization and increased expression of the ER stress marker GRP78-BiP. Inferior portions of these retinas, the areas that exhibited more profound pathological changes, demonstrated significant photoreceptor loss. The superior retina maintained a greater degree of structural integrity, but expressed higher levels of the ER stress marker GRP78-BiP. In 2 month DKO mice, retinal damage was already apparent in the inferior retina with focal disorganization in the outer nuclear layer. As early as 2 months, these mice showed increased levels of ER stress. Retinal sections of 2 month controls showed little ER stress; older controls demonstrated increased labeling. However, control labeling was less than that observed in mutants.
Retinas of these mice contained varying, focal pathological abnormalities. In areas where retinal architecture was relatively conserved, increased expression of ER stress markers was found. Expression of the ER stress marker precedes structural damage in RPE, photoreceptors, and inner retina, implicating ER stress as an important event that precedes photoreceptor loss in the DKO mice. This may be an amenable therapeutic target to explore for AMD.
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