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A Model for Small Heat Shock Protein Inhibition of Polyglutamine Aggregation

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Abstract

Polyglutamine (polyQ) repeat expansions that lead to the formation of amyloid aggregates are linked to several devastating neurodegenerative disorders. While molecular chaperones, including the small heat shock proteins (sHsp), play an important role in protection against protein misfolding, the aberrant protein folding that accompanies these polyQ diseases overwhelms the chaperone network. By generating a model structure to explain the observed suppression of spinocerebellar ataxia 3 (SCA3) by the sHsp αB-crystallin, we have identified key vulnerabilities that provide a possible mechanism to explain this heat shock response. A docking study involving a small bioactive peptide should also aid in the development of new drug targets for the prevention of polyQ-based aggregation.

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Acknowledgments

The authors EFH and CL are grateful to the Welch Foundation (Grant # BH-0018) for its continuing support of the Chemistry Department at St. Edward’s University. We thank Dr. Arthur Olson for the AutoDock 4.0 and AutoGrid 4.0 programs. This paper is dedicated to the memory of Woody Guthrie, who on October 3, 1967 died from complications of Huntington’s disease.

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Authors and Affiliations

  1. Department of Chemistry, St. Edward’s University, Austin, TX, 78704, USA

    Eamonn F. Healy & Carley Little

  2. Department of Biological Sciences, St. Edward’s University, Austin, TX, 78704, USA

    Peter J. King

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  1. Eamonn F. Healy
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  2. Carley Little
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Correspondence to Eamonn F. Healy.

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Healy, E.F., Little, C. & King, P.J. A Model for Small Heat Shock Protein Inhibition of Polyglutamine Aggregation. Cell Biochem Biophys 69, 275–281 (2014). https://doi.org/10.1007/s12013-013-9795-1

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  • DOI: https://doi.org/10.1007/s12013-013-9795-1

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