title: Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease.
abstract: Huntington disease (HD) is a devastating neurodegenerative disorder for which there are no disease-modifying treatments. Previous studies have proposed that activation of the heat shock response (HSR) via the transcription factor heat shock factor 1 (HSF1) may be of therapeutic benefit. However, the effect of disease progression on the HSR and the therapeutic potential of this pathway are currently unknown. Here, we used a brain-penetrating HSP90 inhibitor and physiological, molecular, and behavioral readouts to demonstrate that pharmacological activation of HSF1 improves huntingtin aggregate load, motor performance, and other HD-related phenotypes in the R6/2 mouse model of HD. However, the beneficial effects of this treatment were transient and diminished with disease progression. Molecular analyses to understand the transient nature of these effects revealed altered chromatin architecture, reduced HSF1 binding, and impaired HSR accompanied disease progression in both the R6/2 transgenic and HdhQ150 knockin mouse models of HD. Taken together, our findings reveal that the HSR, a major inducible regulator of protein homeostasis and longevity, is disrupted in HD. Consequently, pharmacological induction of HSF1 as a therapeutic approach to HD is more complex than was previously anticipated.
authors.affiliation: Department of Medical and Molecular Genetics, King’s College London, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Labbadia
authors.forename: Helen
authors.initials: H
authors.lastname: Cunliffe
authors.forename: Andreas
authors.initials: A
authors.lastname: Weiss
authors.forename: Elena
authors.initials: E
authors.lastname: Katsyuba
authors.forename: Kirupa
authors.initials: K
authors.lastname: Sathasivam
authors.forename: Tamara
authors.initials: T
authors.lastname: Seredenina
authors.forename: Ben
authors.initials: B
authors.lastname: Woodman
authors.forename: Saliha
authors.initials: S
authors.lastname: Moussaoui
authors.forename: Stefan
authors.initials: S
authors.lastname: Frentzel
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.forename: Paolo
authors.initials: P
authors.lastname: Paganetti
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D014157:Transcription Factors / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D014157:Transcription Factors