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 of stress proteins (termed ‘heat shock proteins’ or ‘Hsps’) are induced that play roles in cellular repair and protection. Our previous studies have shown that this cellular stress response is physiologically relevant as Hsps are rapidly induced in the nervous system in response to temperature elevation and tissue injury. Hsps are ‘protein repair agents’ that provide a line of defense against misfolded, aggregation-prone proteins that accumulated following cellular stress and during neurodegenerative disorders. HSPA is a multigene family that includes i) stress-inducible Hsp70-1 encoded by the HSPA1A gene and ii) stress-inducible Hsp70B’ encoded by HSPA6 that has received comparatively little attention. The vision of this research proposal is to move the neurobiology of the cellular stress response into a new era. Namely, live imaging of the cellular stress response in neuronal cells grown in tissue culture and, beyond that, to high resolution live imaging in the intact mammalian brain, with a focus on Hsp70B’. Our research group is presently the only laboratory that has reported on expression of Hsp70B’ in neural systems. In October 2014, we reported a novel role of Hsp70B’ that is not observed for Hsp70-1. Hsp70B’ transiently associates with the periphery of nuclear speckles that are sites of transcription during the recovery of neuronal cells from stress-induced transcriptional inhibition. We will now determine if transcriptional recovery after stress is dependent on induction of Hsp70B’ and if the phenomenon is specific to neuronal cells. Stress-sensitive intracellular sites will be identified by live image localization of Hsp70s in cultured neuronal cells by spinning disk microscopy and in the intact brain by multiphoton microscopy. These studies will facilitate real time analysis of the cellular stress response in neural systems. Neuroprotective features of our novel multitarget modulators of neural protein misfolding will be moved into a new realm of analysis in the living brain using the latest multiphoton advances. Trainees participating in the program will benefit from working on novel aspects of the cellular stress response and from the array of advanced technology acquired over the period 2009-2014 with a major CFI/ORF infrastructure award of $5.8 million to the Center for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough.