Neurotoxicity from glutathione depletion is mediated by Cu-dependent p53 activation

摘要: Loss of intracellular neuronal glutathione (GSH) is an important feature neurodegenerative disorders including Alzheimer's disease, Parkinson's and amyotrophic lateral sclerosis. The consequences GSH depletion include increased oxidative damage to proteins, lipids, DNA subsequent cytotoxic effects. also modulator cellular copper (Cu) homeostasis altered Cu metabolism central the pathology several diseases. effects in cells depleted are not well understood. We have previously reported that levels results cell death from trace extracellular due elevated Cu(I)-mediated free radical production. In this study we further examined molecular pathway toxicity neurons fibroblasts GSH. Treatment primary cortical or 3T3 with synthetase inhibitor buthionine sulfoximine resulted substantial loss cytotoxicity. found both revealed expression activation p53 after activity was induced by Cu. Furthermore, showed GSH-depleted cells, increase stress resulting p53-dependent death. These findings may implications for involve aberrant metabolism.