Age-associated oxidative damage leads to absence of gamma-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 gamma-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 gamma-cystathionase activity in the eye lens, and (2) to determine the role of gamma-cystathionase deficiency in cataractogenesis. Two populations of old rats were found, one (56%) whose lenses lacked gamma-cystathionase activity and the rest that exhibited detectable enzyme activity. gamma-Cystathionase protein was absent in lenses from old rats without gamma-cystathionase activity. Oxidative stress targeted gamma-cystathionase in the eye lens upon aging, since the enzyme contained more carbonyl groups in old lenses than in young ones. gamma-Cystathionase mRNA was also markedly reduced in old lenses, thus contributing to the age-associated deficiency in gamma-cystathionase. Inhibition of gamma-cystathionase activity caused glutathione depletion in lenses and led to cataractogenesis in vitro. In conclusion, the lack of gamma-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.
Sastre
Juan
J
Department of Physiology, School of Medicine, University of Valencia, Avda. Blasco Ibañez 17, 46010 Valencia, Spain. juan.sastre@uv.es
Martín
José Antonio
JA
Gómez-Cabrera
Mari-Carmen
MC
Pereda
Javier
J
Borrás
Consuelo
C
Pallardó
Federico V
FV
Viña
José
J
D000375:Aging / Q000502:physiology*; D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D002386:Cataract / Q000209:etiology*; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000276:immunology; D005978:Glutathione / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007908:Lens, Crystalline / Q000201:enzymology*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D000480:Alkynes; C009055:propargylglycine; D003542:Cystathionine gamma-Lyase; D005978:Glutathione; D005998:Glycine