Novel mechanism of HSF1-mediated neuroprotection

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SUMMARY Enhanced activity of the heat shock factor-1 (HSF1) transcription factor has protective effects in a variety of tissue culture and in vivo models of protein aggregation-associated neurodegenerative disease. This neuroprotective effect of HSF1 is thought to be mediated through a stimulation of transcription of genes encoding heat shock proteins (HSPs). By acting as molecular chaperones the newly produced HSPs re-fold or help degrade misfolded proteins in cells that suffer thermal or proteotoxic stress. Stimulation of HSP gene transcription by HSF1 requires its homo-trimerization and binding to sequences called heat shock elements (HSEs) located mostly in the promoters of HSP genes. We recently demonstrated that HSF1 can protect neurons from both proteotoxic and non-proteotoxic death by a mechanism does not require its trimerization and is HSP-independent. The goal of this this proposal is to understand this novel HSP-independent mechanism of neuroprotection. We propose that HSF1 acts by binding to non-HSE sequences as a monomer and regulating genes unconnected to HSPs and other chaperones. We propose that neuroprotection by HSF1 through this non-canonical mechanism requires the activity of histone deacetylases (HDACs) and interaction with the Class III HDAC, SIRT1. The specific aims of our project are: The specific aims of our project are - Aim 1: To understand the role of histone deacetylases in HSF1-mediated neuroprotection. Aim 2: To identify genomic sequences bound by monomeric HSF1 using two separate approaches – ChiP- Seq and Bind-N-Seq. Aim 3: To identify genes regulated by monomeric HSF1 using RNA-Seq. Understanding the mechanism will lead to a better understanding of the process of neurodegeneration and provide the basis for the development of novel therapeutic approaches for neurodegenerative diseases.