Disease Mechanisms - Miscellaneous
Part 5

The Heat-Shock Response

Heat-shock proteins and HD therapeutics

Heat-shock proteins and heat-shock factor 1 may serve as good targets for HD therapeutics. A drug named geldanamycin is known to regulate another heat-shock protein, called hsp90. Hsp90 binds to heat-shock factor 1 and keeps it in an inactive state. Geldanamycin can bind to hsp 90, causing it to release heat-shock factor 1. Then, heat-shock factor 1 activates itself, and stimulates the production of hsp70s present in the cell (see figure 3). These hsp70s then relieve toxicity in the cell (for more on geldanamycin, click here. Radicicol and ansamycin are two other drugs in the same family as geldanamycin. They are used less often, but basically function in exactly the same way.

Another compound called celastrol has recently been identified. Celastrol comes from a plant often used in Chinese herbal medicine for the treatment of fever, chills, rheumatoid arthritis, and bacterial infection. Exposure to celastrol activates heat-shock factor 1, which then triggers the heat-shock response. A celastrol-induced heat-shock response greatly increases the amount of hsp70, hsp40, and small heat-shock proteins in the cell. Collectively, these help reduce mutant huntingtin toxicity in the cell. Scientists are looking further into the structure of celastrol and how it interacts with heat-shock factor 1, and it seems to be a promising treatment.

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J. Seidenfeld, 8/12/06

For further reading:

• Chan HY, et al. “Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy, and modulation of protein solubility in Drosophila." Human Molecular Genetics 2000. 9(19): 2811-2820.
  This is the first paper to describe how heat-shock protein 70 modifies misfolded proteins to be soluble in detergents, despite looking like aggregates under the microscope.
• Hay DG, et al. “Progressive decrease in chaperone protein levels in a mouse model of Huntington’s disease and induction of stress proteins as a therapeutic approach." Human Molecular Genetics 2004. 13(13): 1389 – 1405.
  This is a very technical paper that shows the effects of geldanamycin and radicicol on huntingtin protein aggregates.
• Kim S, et al. “Polyglutamine protein aggregates are dynamic." Nature Cell Biology 2002. 4: 826 – 831
  This article demonstrates the transient binding of heat-shock protein 70 and 40 to protein aggregates.
• Landles C, Bates GP. “Huntingtin and the molecular pathogenesis of Huntington’s disease." EMBO 2004. 5(10): 958 – 963.
  This paper is a good overview of the molecular details of HD, and it also has a few good paragraphs on the role of heat-shock proteins.
• Meriin AB, Sherman MY. “Role of molecular chaperones in neurodegenerative disorders." Int. J. Hyperthermia 2005. 21(5): 403–419.
  This is a complex but thorough review of the roles of molecular chaperones in all steps of neurodegenerative diseases.
• Morimoto RI, et al. “The heat-shock response: regulation and function of heat-shock proteins and molecular chaperones." Essays in Biochemistry 1997. 32: 17- 29
  This is a nice overview of heat shock proteins and molecular chaperone: basic, fairly easy to understand.
• Opal P, Zoghbi HY. “The role of chaperones in polyglutamine disease." Trends in Molecular Medicine 2002. 8(5): 232 – 236.
  A less complex review of the role of heat-shock proteins in polyglutamine diseases.
• Sakahira H, et al. “Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity." PNAS 2002. 99(4): 16412–16418.
  A fairly technical review of polyglutamine aggregation, toxicity, and how heat-shock proteins interact with aggregates.
• Satyal Sh, et al. “Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans" PNAS 2000. 97(11): 5750–5755
  This article shows the effects of heat-shock protein 104 on polyglutamine aggregates.
• Sittler A, et al. Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease." Human Molecular Genetics 2001. 10(12): 1307-15.
  This article shows that treating nerve cells with geldanamycin decreased huntingtin aggregation.
• Westerheide SD, et al. “Celastrols as Inducers of the Heat Shock Response and Cytoprotection." Journal of Biological Chemistry 2004. 279 (53): 56053–56060.
  A fairly technical paper that discusses the identification of celastrol, its affects on the heat-shock response, and implications for treatment.
• Wyttenbach A. “Role of Heat Shock Proteins During Polyglutamine Neurodegeneration: Mechanisms and Hypothesis" Journal of Molecular Neuroscience 2004. 23: 69 – 95.
  This is a fairly technical review that discusses the role of heat shock proteins.

Last Modified: 08/05/2008

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