ENERGY STRESS-INDUCED DOPAMINE LOSS IN GLUTATHIONE PEROXIDASE-OVEREXPRESSING TRANSGENIC MICE AND IN GLUTATHIONE-DEPLETED MESENCEPHALIC CULTURES

The role of the glutathione system in protecting dopamine neurons from a mild impairment of energy metabolism imposed by the competitive suc cinate dehydrogenase inhibitor, malonate, was investigated in vitro an d in vivo. Treatment of mesencephalic cultures with 10 mu M buthionine sulfoxamine for 24 h reduced total glutathione levels in the cultures by 68%. Reduction of cellular glutathione per se was not toxic to the dopamine population, but potentiated toxicity when the cultures were exposed to malonate. In contrast, transgenic mice overexpressing gluta thione peroxidase (hGPE) that received an intrastriatal infusion of ma lonate (3 mu mol) into the left side had significantly less loss of st riatal dopamine than their hGPE-negative littermates when assayed 1 we ek following infusion. These studies demonstrate that manipulation of the glutathione system influences susceptibility of dopamine neurons t o damage due to energy impairment. The findings may provide insight in to the loss of dopamine neurons in Parkinson's disease in which defect s in both energy metabolism and the glutathione system have been ident ified.