Age-associated oxidative damage leads to absence of γ-cystathionase in over 50% of rat lenses: Relevance in cataractogenesis

Oxidative damage to lens proteins and glutathione depletion play a major role in the development of senile cataract. We previously found that a deficiency in γ-cystathionase activity may be responsible for glutathione depletion in old lenses. The aims of this study were: (1) to investigate the mechanism that causes the age-related deficiency in γ-cystathionase activity in the eye lens, and (2) to determine the role of γ-cystathionase deficiency in cataractogenesis. Two populations of old rats were found, one (56%) whose lenses lacked γ-cystathionase activity and the rest that exhibited detectable enzyme activity. γ-Cystathionase protein was absent in lenses from old rats without γ-cystathionase activity. Oxidative stress targeted γ-cystathionase in the eye lens upon aging, since the enzyme contained more carbonyl groups in old lenses than in young ones. γ-Cystathionase mRNA was also markedly reduced in old lenses, thus contributing to the age-associated deficiency in γ-cystathionase. Inhibition of γ-cystathionase activity caused glutathione depletion in lenses and led to cataractogenesis in vitro. In conclusion, the lack of γ-cystathionase activity in over 50% of old lenses is due to decreased gene expression and proteolytic degradation of the oxidized enzyme. This results in a high risk for the development of senile cataract.