Celastrol inhibits polyglutamine aggregation and toxicity though induction of the heat shock response.
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.
Zhang
Yu-Qian
YQ
Department of Molecular and Cellular Biochemistry, University of Kentucky, 741 S. Limestone Street, Lexington, KY 40536, USA.
Sarge
Kevin D
KD
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016716:PC12 Cells; D053978:Pentacyclic Triterpenes; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012995:Solubility; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014315:Triterpenes / Q000494:pharmacology*; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D053978:Pentacyclic Triterpenes; D010455:Peptides; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D014315:Triterpenes; C097188:polyglutamine; C050414:celastrol