Regulation of translation elongation and integrated stress response in heat-shocked neurons

Neurons in the mammalian central nervous system adapt to changes in temperature through molecular mechanisms that are poorly understood. Here, in response to elevated temperatures, we show that primary mouse neurons isolated from the cortex experience a global downregulation of polysome-dependent translation and a concomitant activation of a unique transcriptional program. These new transcripts were found associated with ribosomes during initial stages of this heat-induced stress response, during which time there was little global protein production. Returning neurons to baseline temperature within a defined window of time (<60 minutes) was necessary for translation to return to control levels and ultimately for neuronal survival. Neurons placed at baseline temperature beyond this time window did not recover translation and died. Among the many transcripts upregulated during heat stress, we observed a ~350-fold increase in Hspa1a and yet no detectable translation of Hsp70 protein until recovery at baseline temperature. We considered that this heat stress response was relevant to neuronal resilience and survival following recovery. To begin to test this idea, we chose to use orthogonal approaches to suppress Hsp70 expression or function. We found, in neurons which had experienced heat stress, that Hsp70 was critical for preventing activation of cell death pathways during recovery. Taken together, our findings suggest that neurons are unique in their response to heat stress in that during a finite window they poise ribosomes on new transcripts, such as Hspa1a, thus preparing for exclusive expression of these factors in the event that recovery is an option.