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D. S. Kuo, C. Labelle-Dumais, Y. Weng, D. B. Gould; Elucidation of the Underlying Pathogenic Mechanism in a Novel Model of Age-Related Macular Degeneration: A Role for Endoplasmic Reticulum Stress. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5811.
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Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly of developed countries, affecting over 50 million people worldwide. Inflammation and oxidative stress are proposed to contribute to AMD pathogenesis, but the factors that trigger the activation of these pathways remain elusive. Endoplasmic reticulum (ER) stress can lead to oxidative stress and is one possible mechanism leading to AMD. Misfolded mutant proteins are a source of ER stress and can activate an intracellular signaling pathway called the Unfolded Protein Response. We found that mice with a mutation in the type IV collagen alpha 1 gene (Col4a1Δex40/+) develop AMD-like pathology. In this study, we test the hypothesis that misfolded COL4A1 protein is the primary insult leading to ER stress and, in turn, oxidative stress and subsequent AMD-like pathology in these mice.
To investigate the cellular mechanism underlying the AMD-like phenotype observed in Col4a1 Δex40/+ mice, we isolated mouse embryonic fibroblasts (MEFs) from day 14 Col4a1Δex40/+ and Col4a1 +/+ embryos and evaluated them for intracellular accumulation of COL4A1, COL4A1 secretion, and expression of ER stress markers.
Intracellular accumulation of COL4A1 was absent in Col4a1 +/+ MEFs but always present in Col4a1 Δex40/+ MEFs. A concomitant decrease in COL4A1 secretion was also observed in Col4a1 Δex40/+ MEFs compared to Col4a1 +/+ MEFs. Furthermore, markers of ER stress were increased in Col4a1 Δex40/+ MEFs compared to Col4a1+/+ MEFs.
Collectively, these findings are consistent with misfolded COL4A1 protein-induced ER stress as the pathogenic mechanism underlying the AMD-like phenotype in our mouse model, and suggest a potential role for ER stress in the etiology of AMD that warrants further investigation. Going forward, this mouse model will be a valuable tool to further characterize the involvement of protein misfolding and ER stress in retinal disease and to explore the possibility of targeting this pathway with therapeutic interventions that could prevent or delay vision loss in millions of people.
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