Our work is to understand the regulation and function of the heat shock transcriptional response (HSR) as a proteome quality control (QC) mechanism in the context of neurodegenerative disease pathogenesis and therapeutics.  The rationale and import of this work include: (1) the importance of protein QC in stress resistance and longevity, and (2) defects in protein QC contribute importantly to pathogenesis of age-related neurodegenerative diseases (ND) such as Alzheimer’s, Parkinson’s, Lou Gehrig’s, Huntington’s, and Prion (CJD) diseases.  Our recent studies of the dynamic control of mHtt aggregation and downstream transcription factor function by HSP chaperones and osmolytes provided important insights on mHtt structuring, aggregation, and disease pathogenesis.  We are hopeful that our work can contribute to the building of an intellectual framework for therapeutics development in ND.