Down-regulation of γ-glutamylcysteine synthetase regulatory subunit gene expression in rat brain tissue during aging
Article first published online: 5 APR 2002
Copyright © 2002 Wiley-Liss, Inc.
Journal of Neuroscience Research
Volume 68, Issue 3, pages 344–351, 1 May 2002
How to Cite
Liu, R.-M. (2002), Down-regulation of γ-glutamylcysteine synthetase regulatory subunit gene expression in rat brain tissue during aging. J. Neurosci. Res., 68: 344–351. doi: 10.1002/jnr.10217
- Issue published online: 16 APR 2002
- Article first published online: 5 APR 2002
- Manuscript Accepted: 29 JAN 2002
- Manuscript Revised: 28 JAN 2002
- Manuscript Received: 28 NOV 2001
- National Institutes of Health. Grant Number: 1 R03-AG16029-01
- γ-glutamylcysteine synthetase;
- glutathione synthetase
The mechanism underlying age-related neurodegenerative diseases is still an area of significant controversy. Increased evidence suggests that oxidative stress contributes importantly to neuronal damage observed in the brains of aged animals and in neurodegenerative diseases. Glutathione (GSH), the most abundant intracellular nonprotein thiol, plays an important role in antioxidant defense. The concentration of this important antioxidant decreases with age in the brain, which is accompanied by an increase in oxidative damage to macromolecules. The mechanism underlying the age-associated decline in GSH content in the brain, however, is not clear. In this study, we demonstrate for the first time that the expression of the regulatory subunit of γ-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in de novo GSH synthesis, decreases with age in cerebellum, cerebral cortex, and hippocampus of Fisher 344 rats. This was accompanied by a decline in GCS activity and GSH content. There were no significant differences in either the concentrations of cysteine and glutathione disulfide (GSSG) or the activities of glutathione synthetase (GS), γ-glutamyl traspeptidase (GGT), and glutathione reductase (GR) in the brains from different age groups. Our results suggest that the age-associated decrease in GSH in the brain may result from the down-regulation of GCS regulatory subunit and consequently a decrease in the activity of GCS. © 2002 Wiley-Liss, Inc.