Neuronal cells are highly sensitive to proteo-toxicity and neurodegenerative diseases such as Huntington's, Alzheimer's, Parkinson's and prion-based disease are associated with the presence of inappropriately folded or aggregated proteins. Protein chaperones function in the proper folding, processing and turnover of proteins and serve to protect cells from proteo-toxicity. Experimental evidence in cellular and animal models of neurodegenerative diseases associated with protein misfolding strongly support a potential therapeutic role for elevated protein chaperone expression. The human Heat Shock Transcription Factor 1 (HSF1) coordinately activates both basal and inducible expression of many genes encoding protein chaperones and other proteins that protect cells from stress and cell death, suggesting that HSF1 is an attractive target for pharmacological intervention in neurodegenerative disease. In this application I outline two specific aims that focus on the characterization of novel small molecules and regulatory proteins that could provide a basis for pharmacological intervention to enhance protein chaperone expression. In the first Specific Aim I outline experiments to understand the detailed mechanism of action of a novel small molecule, HSF1A, capable of coordinately inducing protein chaperone expression through the activation of human HSF1. In the second Specific Aim I outline experiments to evaluate the function of HSF1A, and structurally related molecules, in striatal cell culture, a corticostriatal rat brain slice model of Huntington

Public Health Relevance

Neurodegenerative diseases such as Huntington's, Alzheimer's, Parkinson's and Amyotropic Lateral Sclerosis are associated with the presence of misfolded and aggregated proteins. The research proposed in this application aims to characterize novel chemicals and genes that could serve as a basis for the development of therapeutic approaches to ameliorate defects in protein folding associated with human neurodegenerative disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065890-03
Application #
8220871
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sutherland, Margaret L
Project Start
2010-02-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$329,950
Indirect Cost
$115,575
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Jaeger, Alex M; Makley, Leah N; Gestwicki, Jason E et al. (2014) Genomic heat shock element sequences drive cooperative human heat shock factor 1 DNA binding and selectivity. J Biol Chem 289:30459-69
Batista-Nascimento, Liliana; Neef, Daniel W; Liu, Phillip C C et al. (2011) Deciphering human heat shock transcription factor 1 regulation via post-translational modification in yeast. PLoS One 6:e15976
Neef, Daniel W; Jaeger, Alex M; Thiele, Dennis J (2011) Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nat Rev Drug Discov 10:930-44