Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease.
Published online
Journal Article
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.
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Duke Authors
Cited Authors
- Neef, DW; Turski, ML; Thiele, DJ
Published Date
- January 19, 2010
Published In
Volume / Issue
- 8 / 1
Start / End Page
- e1000291 -
PubMed ID
- 20098725
Pubmed Central ID
- 20098725
Electronic International Standard Serial Number (EISSN)
- 1545-7885
Digital Object Identifier (DOI)
- 10.1371/journal.pbio.1000291
Language
- eng
Conference Location
- United States