Heat Shock Proteins and Motoneuron Survival

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DESCRIPTION (provided by applicant): In diseases of the Central Nervous System, the culmination of ineffective responses to stressful stimuli appear to trigger neurodegeneration. The specific reason why selective neuronal populations die in these disorders is unknown. Stressful stimuli can include, excessive changes in metabolic activity, excitotoxicity, toxic insults, or, similar to developmental cell death, loss of or inadequate trophic support. Many of these factors have been hypothesized to contribute to motoneuron death in amyotrophic lateral sclerosis (ALS), a disease characterized by motoneuron injury and death. Furthermore, there also appears to be altered or ineffective responses to stressful stimuli by the glial cells in affected tissue, implying a decline in glial function. In this proposal, we plan to examine the role of glia in neuroprotection following stress. This potentially critical neuronal-glial interaction involves production and secretion of heat shock proteins (Hsps) by glia, and utilization of these exogenous proteins by neurons. Our preliminary data indicate that motoneurons deprived of trophic factors show no detectable change in endogenous heat shock proteins as compared to healthy spinal motoneurons. Interestingly, the addition of exogenous heat shock proteins to the culture medium is extremely effective at promoting motoneuron survival in the absence of trophic support. There are two central hypotheses of this proposal. The first is that extracellular heat shock proteins promote motoneuron survival following stressful stimuli in vivo. The second hypothesis is that glial cells secrete these proteins. The purpose of this proposal is to test this hypothesis by examining neurons and glia in culture under stress conditions, and determining the role of heat shock proteins in neuronal survival. The first Aim of this proposal will serve to first gather appropriate baseline data for Hsp expression in spinal motoneurons subjected to stressful stimuli in culture. The second Aim will address the role played by Hsps from an extracellular source in neuroprotection following stress. The third Aim will establish the connection in vitro between Hsps secreted by astrocytes and neuronal protection from stressful stimuli. Taken together, these experiments will form a strong basis both for future experiments exploring the fundamental nature of the interactions of neurons and glia, and on ways to exploit that knowledge for the treatment of neurodegenerative diseases.