title: 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.
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Jackrel
authors.forename: James
authors.initials: J
authors.lastname: Shorter
mesh_terms: D000818:Animals; D002843:Chromatin / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D014644:Genetic Variation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000502:physiology; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008954:Models, Biological; D010641:Phenotype; D017510:Protein Folding; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D014157:Transcription Factors