Molecular Analysis of Neurotoxin Induced Apoptosis

Apoptotic cell-death in the brain is a common feature in a variety of neurodegenerative diseases and following exposure to neurotoxins. We hypothesize that certain components of the signaling pathways activated by pathophysiological stimuli might be shared and could serve as targets for the development of therapeutic approaches. In our application, we proposed to compare the signaling pathways activated by four different apoptotic stimuli using cultures of rat cerebellar granule neurons with the goal of identifying common signaling molecules. During the first three years, our goal was to use one of these apoptotic stimuli - potassium (K+) deprivation - and examine the role of four different apoptosis-regulatory molecules. We have now confirmed that NF-kB is a molecule central to neuronal survival and have obtained substantial information regarding the mechanism by which NF-kB activity is regulated in neurons undergoing apoptosis. We show that NF-kB activity is also affected by the neurotoxins, methylmercury and 6-hydroxydopamine. We have gathered evidence indicating that p38-beta activation is necessary for neuronal survival. We show that Akt is necessary for the survival promoting effect of IGF-l, but not of K+. In research that has just been published, we show that contrary to common belief, Akt lies downstream and not downstream of NF-kB activation.