Shock and awe: unleashing the heat shock response to treat Huntington disease

Abstract

The heat shock response (HSR) is a highly conserved protective mechanism that enables cells to withstand diverse environmental stressors that disrupt protein homeostasis (proteostasis) and promote protein misfolding. It has been suggested that small-molecule drugs that elicit the HSR by activating the transcription factor heat shock factor 1 might help mitigate protein misfolding and aggregation in several devastating neurodegenerative disorders, including Huntington disease (HD). In this issue of the JCI, Labbadia et al. use a brain-penetrant Hsp90 inhibitor, HSP990, to induce the HSR in mouse models of HD. Unexpectedly, they observed that HSP990 confers only transient amelioration of a subset of HD-related phenotypes, because alterations in chromatin architecture impair the HSR upon disease progression. These findings suggest that synergistic combination therapies that simultaneously unleash the HSR and prevent its impairment are likely to be needed to restore proteostasis in HD.

Figure 1. HSR activation varies with disease stage in mice that model HD.

Upon inhibition of Hsp90 by the small molecule HSP990, the HSR is activated via HSF1. HSF1 dissociates from its repressive complex with Hsp90, is hyperphosphorylated, and translocates to the nucleus in both early- and late-stage HD mice. As HD progresses and the mice age, histone H4 becomes hypoacetylated at heat shock (HS) gene promoters, preventing efficient transcription of the heat shock genes and impairing the HSR. While early-stage HD mice induce an HSR upon HSP990 treatment and reduce the aggregate burden, late-stage HD mice cannot induce the HSR, and the aggregate burden and toxicity increases. HSE, heat shock element.