Emerging Non-canonical Roles of Heat Shock Transcription Factor 1 in Synaptic Gene Regulation in Combating Neurodegeneration

Heat shock factor 1 (HSF1) is arguably the most important master regulator orchestrating every aspect of our cellular stress response in virtually all cells. Besides the classic role of HSF1 in transcriptional upregulation of the genes encoding for heat shock proteins (HSPs) during the heat shock response (HSR), numerous non-HSP-related target genes and functions have been identified, including multiple synaptic genes involved in brain functions of learning and memory. Herein, we will focus on reviewing the roles of HSF1 in synaptic regulation and in memory formation. Specifically, we will 1) revisit the Hsf1-null mouse genetic data and discuss the implication of HSF1 in neurodegeneration; 2) review evidence supporting HSF1’s novel role in memory formation; 3) review the recently confirmed HSF1 direct gene targets concerning synaptic plasticity and memory formation; 4) discuss therapeutic considerations of HSF1-based strategies in treating cognitive decline. Although we will designate the majority of this review to the emerging non-canonical roles of HSF1 in regulating genes beyond the HSR process (i.e., non-HSP genes), we will also include recent conceptual advance in the area of HSF1 at the crossroad between cancer and neurodegeneration via countering amyloidogenesis. Lastly, we will briefly discuss how we may utilize the cutting-edge technology of multi-omics in the future to fill the current knowledge gaps in HSF1 biology in the mouse brain during aging and neurodegeneration.