Mechanisms of Resistance to Neurotoxins
Final rept. 1 Sep 1999-31 Aug 2002
SALK INST FOR BIOLOGICAL STUDIES LA JOLLA CA
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The toxicity of chemically reactive oxygen species ROS is thought to make a significant contribution to the death of nerve cells caused by many neurotoxins as well as in stroke and Parkinsons disease. During all of these events, some groups of nerve cells are spared relative to others. It is therefore likely that biochemical mechanisms exist which lead to increased resistance to oxidative stress and other forms of cytotoxicity. It was the goal of this proposal to understand how nerve cells defend themselves against neurotoxins that kill cells via ROS and oxidative stress. To accomplish this goal, we have studied toxin sensitive cell death pathways and have selected groups of cells which are very resistant to ROS generated in a model system which mimics some aspects of acute neurotoxicity and stroke. It was shown that the translation factor eIF2alpha mediates cell death involving oxidative stress, while the classical pro-apoptosis factor Bax is not involved. The activation of soluble guanylate cyclase is also required for cell death, for dopamine D4 receptor activation inhibits cGMP production and blocks cell death. Other inhibitors of oxidative stress induced nerve cell death were also discovered. These include a unique group of plant flavanoids and the activation of the transcription factor HIF-1. Finally, it was shown that while there is a great deal of cross-resistance to many neurotoxins, the components of the cell death pathways are sometimes distinct.
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