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J. Biol. Chem., Vol. 280, Issue 39, 33097-33100, September 30, 2005
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Minireview
Heat Shock Response Modulators as Therapeutic Tools for Diseases of Protein Conformation*
From the Department of Biochemistry, Molecular Biology, and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208
The disruption of protein folding quality control results in the accumulation of a non-native protein species that can form oligomers, aggregates, and inclusions indicative of neurodegenerative disease. Likewise for over 100 other human diseases of protein confirmation, a common feature may be the formation of off-pathway folding intermediates that are unstable, self-associate, and with time lead to a chronic imbalance in protein homeostasis with deleterious consequences on cellular function. This has led to a hypothesis that enhancement of components of the cellular quality control machinery, specifically the levels and activities of molecular chaperones, suppress aggregation and toxicity phenotypes to allow cellular function to be restored. This review addresses the regulation of molecular chaperones and components of protein homeostasis by heat shock transcription factor 1 (HSF1), the master stress-inducible regulator, and our current understanding of pharmacologically active small molecule regulators of the heat shock response as a therapeutic strategy for protein conformational diseases.
* This minireview will be reprinted in the 2005 Minireview Compendium, which will be available in January, 2006. This work was supported by grants from the National Institute for General Medical Science, National Institutes for Neurological Diseases and Stroke, Rice Institute for Biomedical Research, Huntington Disease Society of America Coalition for the Cure, and Amyotrophic Lateral Sclerosis Association (ALSA) (to R. I. M.), and National Institutes of Health Training Grant in Signal Transduction and Cancer T32 CA70085 (to S. D. W.).
1 To whom correspondence should be addressed. Tel.: 847-491-3340; Fax: 847-491-4461; E-mail: r-morimoto{at}northwestern.edu.
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