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 6

Reduced HSF1 promoter binding and altered nucleosome landscapes are observed at HS loci in R6/2 mice, but do not correlate with chromatin accessibility.

Options: View larger image (or click on image) Download as PowerPoint
Reduced HSF1 promoter binding and altered nucleosome landscapes are obse...
(A–E) Levels of HSF1 (A and D), RNA polymerase 2 (RNApol2), H3AcK9, H3AcK27 (B), and Tetra AcH4 (C and E) bound to HS promoters 2 hours after vehicle or HSP990 treatment (12 mg/kg) was determined by ChIP in 12-week-old WT and R6/2 (A–C) and 22-month-old WT and HdhQ150/Q150 (D and E) mouse half brains. Chromatin was immunoprecipitated, and SYBR green qPCR was performed on the resulting DNA with primers specific for the Hspa1b, Hspb1, and Dnajb1 promoters. Signal was normalized to 10% of the input for each sample. Values are mean ± SEM (n = 5 per treatment group). Black lines in A–E indicate mean signal obtained after pulldown with rabbit IgG alone (n = 2). (F) MNase digestion was performed on chromatin extracted from mouse brain tissue 2 hours after treatment with vehicle or HSP990. SYBR green was then performed using primers spanning the Hspa1b gene. Digested signal was normalized to undigested signal, and values are mean ± SEM (n = 4 per treatment group). *P < 0.05 vs. WT HSP990, #P < 0.05 vs. WT vehicle, Student’s t test.