Celastrol inhibits polyglutamine aggregation and toxicity though induction of the heat shock response

Yu Qian Zhang, Kevin D. Sarge

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

Heat shock proteins (hsps) are protective against the harmful effects of mutant expanded polyglutamine repeat proteins that occur in diseases such as Huntington's, prompting the search for pharmacologic compounds that increase hsp expression in cells as potential treatments for this and related diseases. In this paper, we show that celastrol, a compound recently shown to up-regulate hsp gene expression, significantly decreases killing of cells expressing mutant polyglutamine protein. This effect requires the presence of the transcription factor responsible for mediating inducible hsp gene expression, HSF1, and is correlated with decreased amounts and increased sodium dodecyl sulfate (SDS) solubility of polyglutamine aggregates. These results suggest the potential of celastrol as a therapeutic agent in the treatment of human polyglutamine expansion diseases.

Original languageEnglish
Pages (from-to)1421-1428
Number of pages8
JournalJournal of Molecular Medicine
Volume85
Issue number12
DOIs
StatePublished - Dec 2007

Bibliographical note

Funding Information:
Acknowledgements We would like to thank Dr. James Burke for providing polyglutamine-YFP plasmid constructs, Dr. Ivor Benjamin for providing the HSF1+/+ and HSF1−/− MEF cells, and Dr. Doug Andres for providing PC12 cells. We also thank the other members of our laboratory for insightful discussions during the course of this work. This work was supported by NIH grants GM61053 and GM64606 to K.D.S.

Keywords

  • Aggregates
  • Celastrol
  • HSF1
  • Heat shock proteins
  • Polyglutamine
  • hsp70

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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