期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 121, 期 8, 页码 2972-2975出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI59190
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资金
- NIH HHS [1DP2OD002177-01, DP2 OD002177] Funding Source: Medline
- NINDS NIH HHS [5R21NS067354-02, R21 NS067354] Funding Source: Medline
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.
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