Mechanisms of Resistance to Neurotoxins
Abstract
Glutamic acid is both a neurotransmitter in the brain as well as a major neurotoxin, killing nerve cells during trauma and ischemia. Glutamate kills cells through receptor mediated excitotoxicity or via an oxidative stress pathway called oxidative glutamate toxicity. During the past year our laboratory has been studying the pathways which lead to glutamate induced cell death by the oxidative pathway. Using an expression cloning strategy, we have identified a protein, the translation initiation factor alpha IF2 alpha, which acts as a central switch that determines whether cells live or die in response to oxidative stress. This appears to be done by the ability of eIF2 alpha to control the rate of glutathione synthesis by the translational regulation of the rate limiting enzyme in glutathione synthesis. An excellent model for glutamate excitotoxicity was also developed, and it was shown that oxidative glutamate toxicity is a component of the excitotoxicity cascade, a result which explains a great deal of confusing data on glutamate neurotoxicity. Finally, using Bax knock-out mice, we have ruled out the role of this classical death gene in the programmed cell death caused by both forms of glutamate toxicity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2000
- Accession Number
- ADA384832
Entities
People
- David R. Schubert
Organizations
- Salk Institute for Biological Studies