title: Heat shock response activation exacerbates inclusion body formation in a cellular model of Huntington disease.
abstract: The cellular heat shock response (HSR) protects cells from toxicity associated with defective protein folding, and this pathway is widely viewed as a potential pharmacological target to treat neurodegenerative diseases linked to protein aggregation. Here we show that the HSR is not activated by mutant huntingtin (HTT) even in cells selected for the highest expression levels and for the presence of inclusion bodies containing aggregated protein. Surprisingly, HSR activation by HSF1 overexpression or by administration of a small molecule activator lowers the concentration threshold at which HTT forms inclusion bodies in cells expressing aggregation-prone, polyglutamine-expanded fragments of HTT. These data suggest that the HSR does not mitigate inclusion body formation.
authors.affiliation: Department of Biology, Stanford University, Stanford, California 94305, USA.
authors.forename: Kirill
authors.initials: K
authors.lastname: Bersuker
authors.forename: Mark S
authors.initials: MS
authors.lastname: Hipp
authors.forename: Barbara
authors.initials: B
authors.lastname: Calamini
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.forename: Ron R
authors.initials: RR
authors.lastname: Kopito
mesh_terms: D004268:DNA-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D002479:Inclusion Bodies / Q000378:metabolism*; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D050505:Mutant Proteins; D014157:Transcription Factors
keywords: Flow Cytometry; Heat Shock Protein; Heat Shock Response; Huntington Disease; Molecular Chaperone; Protein Aggregation