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.
View: Text | PDF
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

×

Figure 1

NVP-HSP990 elicits an HSR in mouse brain after acute oral administration.

Options: View larger image (or click on image) Download as PowerPoint
NVP-HSP990 elicits an HSR in mouse brain after acute oral administration...
(A) Western blots of HSR and UPR proteins in 10-week-old WT mouse cortex 20 hours after treatment with HSP990 (12 mg/kg) or vehicle. (B) Fold upregulation of HSPs in HSP990-treated WT mice (black) was calculated relative to vehicle-treated WT mice (white) by densitometry. Values are mean ± SEM fold induction (n = 6 per treatment group). (C) Mouse cortices (WT) were harvested 0, 0.5, 1, 2, 4, and 8 hours after a single dose of HSP990 (12 mg/kg) or vehicle. Taqman RT-qPCR was used to determine the fold induction of HS genes relative to expression in the vehicle group 0 hours after dosing. Values (mean ± SEM) were calculated by the ΔCt method, normalized to the housekeeping gene Atp5b (n = 4 per treatment group). (D) Western blotting for HSF1 in cortices of 10-week-old WT mice harvested 1, 2, and 4 hours after an acute dose of HSP990 (12 mg/kg) or vehicle (n = 3 per treatment group). HSF1-P, hyperphosphorylated form of HSF1. Lanes were run on the same gel but were noncontiguous (white lines). **P < 0.01, ***P < 0.001, Student’s t test.