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E. Rajan, C. J. Madson, M. L. Mulhern, J. Usukura, T. Shinohara; Activation of the Unfolded Protein Response (UPR) in Age-Related Cataract Lenses. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3817.
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Age-related cataracts (ARCs) are a multi-factorial disease with a poorly understood etiology. Oxidative stress, combined with aging of the lens is believed to contribute to ARC formation, but sources of the reactive oxygen species (ROS) remain elusive. The unfolded protein response (UPR) activates the production of ROS in various tissues. So far there is no information whether human ARCs are associated with activation of the UPR and ROS productions in LECs. Here we investigated the presence of UPR-specific proteins in the lenses of ARCs.
Pairs of clear human lenses from different age groups and various types of ARC lenses were obtained from the National Disease Research Interchange (NDRI; Philadelphia, PA). One lens from each pair was used for protein analysis and the other lens was used for immunohistochemical analysis. Masspectroscopic analysis was used to authenticate UPR-specific proteins after purification with antibody precipitation and SDS-PAGE fluctuation.
Protein blot analysis showed that clear lenses at ages 17, 30, 44, 63, and 74 did not have apparently detectible levels of UPR-specific proteins. In contrast, in ARCs at similar age groups, significantly higher levels of UPR-specific proteins were found including; ATF4, ATF6, PERK, IRE1α, Bip, CHOP, Calnexin, procaspase-12, eIF2α, and JNK1. Catalytic enzymes for the production of ROS in the UPR such as PDI, Ero1-Lα, and Ero1-Lβ were also significantly elevated in ARCs. Immunohistochemistry of the lens thin sections showed multiple immune-positive staining bands in the outer cortex lens fiber layers of the ARCs but not in the clear lenses. Since, ER stress is induced only in LECs, ROS must come from LECs. We will further discuss potential mechanisms of an activation of the UPR and the production of ROS.
The UPR activation might play a significant role in human ARCs. Our results further suggest that peripheral LECs under ER stress produce ROS to further oxidize the lens.
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