Purchase this article with an account.
P.H. Frederikse, Q. Sun, G. Li, P. Farnsworth, S. Zigler, Jr.; Copper, Copper Binding Amyloid Disease Proteins, and Dityrosine Increase in a Congenital Cataract Model Linked with Oxidative Stress . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3487.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Purpose: As key mechanisms contributing to age-related degenerative diseases involve metal-binding amyloid protein effects on copper homeostasis and oxidative stress, we have examined copper, copper binding amyloid disease proteins and dityrosine in a congenital guinea pig cataract model that is linked with oxidative stress. Previously we demonstrated lens degeneration and cataract in a classic Alzheimer’s disease transgenic mouse model, and in separate studies demonstrated upregulation of Alzheimer precursor protein, beta-amyloid (Abeta) and Prion protein (PrP) by oxidative stress in lenses and lens cells. In addition, copper accumulates in age-related cataracts in humans and other mammals. Methods: Histochemistry, and immunohistochemistry were used to localize copper, superoxide dismutase (SOD), PrP, and Abeta in strain 13N guinea pigs that carry a deletion in the zeta-crystallin gene. Dityrosine antibodies (gift of Y. Kato; Hyogo, Japan) were used to detect dityrosine. Zeta-crystallin is normally expressed in guinea pig lenses and binds NADPH stoichiometrically providing critical reducing power for oxidative stress defenses, and strain 13N mutants exhibit a highly reproducible congenital cataract. Results: We demonstrate greatly increased copper in mutant lenses with a broad distribution that overlaps that of Abeta, PrP and SOD1, all of which are increased. Dityrosine formation, specifically linked with copper and H2O2, is a specific biomarker of protein oxidation in aging and disease. Dityrosine also greatly increased and co-localized with increased copper and copper binding amyloid proteins in mutant lenses. Conclusions: The data are consistent with a role for copper-binding amyloid disease proteins in increasing copper levels and oxidative stress that contribute to cataract formation. These associations may also be operative in human age-dependent cataracts where copper also accumulates, PrP, Abeta and SOD1 are expressed, and oxidative stress is a primary etiologic factor.
This PDF is available to Subscribers Only