Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease
John Labbadia, … , Paolo Paganetti, Gillian P. Bates
John Labbadia, … , Paolo Paganetti, Gillian P. Bates
Published July 25, 2011
Citation Information: J Clin Invest. 2011;121(8):3306-3319. https://doi.org/10.1172/JCI57413.
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Research Article

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

John Labbadia, Helen Cunliffe, Andreas Weiss, Elena Katsyuba, Kirupa Sathasivam, Tamara Seredenina, Ben Woodman, Saliha Moussaoui, Stefan Frentzel, Ruth Luthi-Carter, Paolo Paganetti, Gillian P. Bates

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Figure 4

Impaired upregulation of HSPs occurs at the level of transcription.

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Impaired upregulation of HSPs occurs at the level of transcription. Taqm...
Taqman RT-qPCR of Hspa1a/b, Hspb1, and Dnajb1 was performed on half brains of 12-week-old WT and R6/2 mice 0, 4, or 8 hours after treatment with vehicle or HSP990 (12 mg/kg) (A), or on half brains of 22-month-old WT and HdhQ150/Q150 mice 2 hours after treatment with vehicle or HSP990 (B). (Due to the reduced availability of mice aged 22 months, HdhQ150/Q150 analysis was performed at 2 hours after dose to allow investigation of mRNA levels and chromatin architecture on the same samples.) Chaperone mRNA expression levels were normalized to the housekeeping gene Atp5b. Fold induction of each HS gene after HSP990 treatment was calculated relative to expression levels of WT vehicle groups 0 hours after treatment, and expressed as mean fold ± SEM (n = 4 per treatment group). *P < 0.05, **P < 0.01, ***P < 0.001, Student’s t test.