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dc.contributor.author Neef, DW
dc.contributor.author Turski, ML
dc.contributor.author Thiele, DJ
dc.coverage.spatial United States
dc.date.accessioned 2011-06-21T17:31:05Z
dc.date.issued 2010-01-19
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/20098725
dc.identifier.citation PLoS Biol, 2010, 8 (1), pp. e1000291 - ?
dc.identifier.uri http://hdl.handle.net/10161/4442
dc.description.abstract 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.
dc.format.extent e1000291 - ?
dc.language eng
dc.language.iso en_US en_US
dc.relation.ispartof PLoS Biol
dc.relation.isversionof 10.1371/journal.pbio.1000291
dc.subject Animals
dc.subject Cell Nucleus
dc.subject Cells, Cultured
dc.subject DNA-Binding Proteins
dc.subject Drosophila
dc.subject HSP90 Heat-Shock Proteins
dc.subject Humans
dc.subject Mice
dc.subject Molecular Chaperones
dc.subject Neurodegenerative Diseases
dc.subject Phosphorylation
dc.subject Protein Folding
dc.subject Saccharomyces cerevisiae
dc.subject Transcription Factors
dc.title Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US
duke.date.pubdate 2010-1-0 en_US
duke.description.endpage e1000291 en_US
duke.description.issue 1 en_US
duke.description.startpage e1000291 en_US
duke.description.volume 8 en_US
dc.relation.journal Plos Biology en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/20098725
pubs.issue 1
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Biochemistry
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Molecular Genetics and Microbiology
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Pharmacology & Cancer Biology
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers
pubs.organisational-group /Duke/School of Medicine/Institutes and Centers/Duke Cancer Institute
pubs.publication-status Published online
pubs.volume 8
dc.identifier.eissn 1545-7885

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