Celastrol inhibits polyglutamine aggregation and toxicity though induction of the heat shock response
Open Access
- 18 October 2007
- journal article
- research article
- Published by Springer Nature in Journal of Molecular Medicine
- Vol. 85 (12), 1421-1428
- https://doi.org/10.1007/s00109-007-0251-9
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.This publication has 34 references indexed in Scilit:
- Genetic interaction between expanded murine Hdh alleles and p53 reveal deleterious effects of p53 on Huntington's disease pathogenesisNeurobiology of Disease, 2006
- New Directions for Neurodegenerative Disease Therapy: Using Chemical Compounds to Boost the Formation of Mutant Protein InclusionsCell Cycle, 2006
- Active HSF1 Significantly Suppresses Polyglutamine Aggregate Formation in Cellular and Mouse ModelsJournal of Biological Chemistry, 2005
- Role of molecular chaperones in neurodegenerative disordersInternational Journal of Hyperthermia, 2005
- Modulation of neurodegeneration by molecular chaperonesNature Reviews Neuroscience, 2005
- Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal deathNature, 2004
- A cell-based screen for drugs to treat Huntington's diseaseNeurobiology of Disease, 2004
- A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptorHuman Molecular Genetics, 2003
- Roles of the heat shock transcription factors in regulation of the heat shock response and beyondThe FASEB Journal, 2001
- Oligomerization of Expanded-Polyglutamine Domain Fluorescent Fusion Proteins in Cultured Mammalian CellsBiochemical and Biophysical Research Communications, 1997