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.

Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity

“…Protein lysates were prepared from 4-, 8-, and 14-wk-old R6/2 transgenic mouse brains and wild-type controls and analyzed by SDS-PAGE and immunoblotting. In 14-wk-old transgenic R6/2 mice, which show a severe disease phenotype (Labbadia et al 2011), levels of CRMP1 were significantly reduced compared to age-matched controls (Fig. 2C, D), consistent with the results from the YAC128 HD model ( Fig.…”

Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts

“…This phenomenon, in which an initially robust heatshock response becomes progressively impaired in polyQ diseased animals of advanced age, is thought to arise from histone hypoacetylation, resulting in a decrease in heat-shock gene transcription over time. 31 The initial increase in mouse brain and the observed increase in our patient-derived fibroblasts may represent a general response to cellular stress not specific to neurons. Cellular stress from accumulation of mutant polyQ protein is well established (reviewed in Huen et al 32 ).…”

Proteostasis impairment in protein-misfolding and -aggregation diseases

“…Conversely, the chronic presence of aggregates can suppress the ability of cells to adequately respond to stress [48], supporting the view that protein aggregation is a major driver of the aging process. Studies in mice showed that small molecule activators of the stress response, while effective early in disease, may lose efficacy during disease progression and aging [98]. On the other hand, sustained aggregate stress may result in a disproportionate response.…”