DECREASED GLUTATHIONE RESULTS IN CALCIUM-MEDIATED CELL-DEATH IN PC12

Neuronal damage in certain cellular populations in the brain has been linked to oxidative stress accompanied by an elevation in intracellula r calcium. Many questions remain about how such oxidative stress occur s and how it affects calcium homeostasis. Glutathione (GSH) is a major regulator of cellular redox status in the brain, and lowered GSH leve ls have been associated with dopaminergic cell loss in Parkinson's dis ease (PD). We found that transfection of antisense oligomers directed against glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis, into PC12 cells resulted in decreased GSH and increase d levels of ROS. Decreased GSH levels also correlated with an increase in intracellular calcium levels. Data from this study suggest that do paminergic neurons are very sensitive to decreases in the internal oxi dant buffering capacity of the cell caused by reductions in GSH levels , and that alterations in this parameter can result in disruption of c alcium homeostasis and cell death. These results may be of particular significance for therapeutic treatment of PD, as those dopaminergic ne urons that are spared in this disorder appear to contain the calcium b inding protein, calbindin. (C) 1997 Elsevier Science Inc.