Heat shock proteins in the nervous system

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In response to stressful stimuli, cells activate a highly conserved 'heat shock response' in which a set heat shock proteins (Hsps) are induced. These Hsps are involved in repair and protective mechanisms that permit cells to survive temperature shocks that would normally kill them. We have demonstrated that this response is physiologically relevant as Hsps are rapidly induced in the nervous system in response to fever-like stress or tissue injury. Although the molecular biology of this response has been investigated for many years, little progress has been made on the mechanisms by which Hsps protect neural cells at the functional level. Our laboratory studies neuroprotective effects of Hsps at the level of the synapse. The rationale for looking at synaptic function is that synapses are critical points of information transfer in the nervous system and their functionality needs to be preserved during periods of stress to prevent communication breakdown. This work demonstrates that prior heat shock, sufficient to induce Hsps, protects the nervous system at the level of neurotransmission and that Hsp overexpression enhances the level of synaptic protection. Our hypothesis is that stress perturbs synaptic proteins and that Hsps bind to these targets to facilitate conformational correction. Hsps serve as 'protein repair agents' that provide a line of defense against aggregation-prone proteins. The objectives of the research plan are- i) identify the synaptic binding partners of Hsps to characterize key proteins in the neurotransmission cascade that are 'weak links' susceptible to stress-induced perturbation yet amenable to repair and protection by manipulation of the stress response, ii) employ advanced 'live-cell imaging' to investigate the expression of Hsps and their association with synapses in tissue culture systems and in the intact animal. The work will advance our knowledge of how Hsps protect the nervous system at a functional level. Trainees participating in this program will greatly benefit from the array of new technology purchased with a major CFI/ORF infrastructure award of $5.8 million. Support from NSERC Discovery Grants fostered the programmatic foundation that provided the leverage for the 2009 infrastructure award.