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J. Tuo, R. I. Kevin, M. Zhou, D. Shen, R. J. Ross, C. M. Bojanowski, R. N. Fariss, C. Yin, Z. Zhuang, C.-C. Chan; Aberrant Endoplasmic Reticulum Proteins in Ccl2/Cx3cr1 Deficient Mice With Retinal Degeneration Mimicking Human Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3010.
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Age-related macular degeneration (AMD) involves the degeneration of photoreceptors, retinal pigment epithelium (RPE), Bruch’s membrane, and macular choriocapillaries, resulting in the loss of central vision. We developed an AMD model, Ccl2-/-/Cx3xr1-/- mouse, which displays AMD-like lesions including drusen, RPE hypopigmentation and accumulation of lipofuscin, photoreceptor degeneration, and choroidal neovascularization. This study aimed to detect possible causal factors directly contributing to the retinal phenotype of Ccl2-/-/Cx3xr1-/-.
The study was conducted in compliance with ARVO statement for the use of animals. Mass spectrometry-coupled proteomics followed by RT-PCR gene expression assay, immunochemistry, and Western blotting were used to determine the gene expression profile of the retinal tissue of the wild type and Ccl2-/-/Cx3cr1-/-.
The proteomics showed that 4 proteins were differentially expressed in the retina of Ccl2/Cx3cr1 deficient mice in comparison with the wild type. Mass spectrophotometer confirmed that two of them were ERp29 precursor and CBP140, proteins from endoplasmic reticulum (ER). Further comparison of the expression of various ER proteins between wild type controls and Ccl2-/-/Cx3cr1-/- indicated that ERp29 and CBP140 significantly down-regulated in the retina of Ccl2-/-/Cx3cr1-/-. RT-PCR confirmed an approximate 2-fold downregulation in ERp29 and CBP140 mRNA in Ccl2-/1/Cx3cr1-/- compared to wild type. Immunochemestry and Western Blotting also indicated that ERp29 was expressed at low level in the Ccl2-/-/Cx3cr1-/- retina.
Our data identified at least 2 ER proteins that are associated with an AMD-like phenotype in Ccl2-/-/Cx3cr1-/-. ER protein functions as chaperone in protein folding and maturation. Improper function of ER leads to the accumulation of unfolded protein, which is believed to be the machism of several age-related or neurodegenerative diseases including AMD. The involvement of ER stress in AMD pathogenesis has been reported. ERp29 is one such ER-resident chaperone, which prevents protein aggregation by keeping the unfolded proteins in a folding-competent state and functions as a component of the ER-specific protein-degrading apparatus to eliminate denatured proteins. We expect that the ER and ER-related proteins might play a role in the retinal phenotype of the Ccl2-/-/Cx3cr1-/-.
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