Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease.
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Neurodegenerative diseases such as Huntington disease are devastating disorders with no therapeutic approaches to ameliorate the underlying protein misfolding defect inherent to poly-glutamine (polyQ) proteins. Given the mounting evidence that elevated levels of protein chaperones suppress polyQ protein misfolding, the master regulator of protein chaperone gene transcription, HSF1, is an attractive target for small molecule intervention. We describe a humanized yeast-based high-throughput screen to identify small molecule activators of human HSF1. This screen is insensitive to previously characterized activators of the heat shock response that have undesirable proteotoxic activity or that inhibit Hsp90, the central chaperone for cellular signaling and proliferation. A molecule identified in this screen, HSF1A, is structurally distinct from other characterized small molecule human HSF1 activators, activates HSF1 in mammalian and fly cells, elevates protein chaperone expression, ameliorates protein misfolding and cell death in polyQ-expressing neuronal precursor cells and protects against cytotoxicity in a fly model of polyQ-mediated neurodegeneration. In addition, we show that HSF1A interacts with components of the TRiC/CCT complex, suggesting a potentially novel regulatory role for this complex in modulating HSF1 activity. These studies describe a novel approach for the identification of new classes of pharmacological interventions for protein misfolding that underlies devastating neurodegenerative disease.
HSP90 Heat-Shock Proteins
Published Version (Please cite this version)10.1371/journal.pbio.1000291
Publication InfoNeef, Daniel W; Turski, Michelle L; & Thiele, Dennis J (2010). Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease. PLoS Biol, 8(1). pp. e1000291. 10.1371/journal.pbio.1000291. Retrieved from https://hdl.handle.net/10161/4442.
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George Barth Geller Distinguished Professor of Immunology
Stress genes in cellular homeostasis and disease All organisms are exposed to stressful conditions including elevated temperatures, reactive oxygen species and other metabolites generated by normal biochemical reactions, rapid cellular proliferation, infection, inflammation, pharmacological agents or other pathophysiological states. These stressful conditions can lead to protein misfolding and aggregation, disruption of cellular signaling pathways, cellular dysfunction and