Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach

Hum Mol Genet. 2004 Jul 1;13(13):1389-405. doi: 10.1093/hmg/ddh144. Epub 2004 Apr 28.


The manipulation of chaperone levels has been shown to inhibit aggregation and/or rescue cell death in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster and cell culture models of Huntington's disease (HD) and other polyglutamine (polyQ) disorders. We show here that a progressive decrease in Hdj1, Hdj2, Hsp70, alphaSGT and betaSGT brain levels likely contributes to disease pathogenesis in the R6/2 mouse model of HD. Despite a predominantly extranuclear location, Hdj1, Hdj2, Hsc70, alphaSGT and betaSGT were found to co-localize with nuclear but not with extranuclear aggregates. Quantification of Hdj1 and alphaSGT mRNA levels showed that these do not change and therefore the decrease in protein levels may be a consequence of their sequestration to aggregates, or an increase in protein turnover, possibly as a consequence of their relocation to the nucleus. We have used genetic and pharmacological approaches to assess the therapeutic potential of chaperone manipulation. Ubiquitous overexpression of Hsp70 in the R6/2 mouse (as a result of crossing to Hsp70 transgenics) delays aggregate formation by 1 week, has no effect on the detergent solubility of aggregates and does not alter the course of the neurological phenotype. We used an organotypic slice culture assay to show that pharmacological induction of the heat shock response might be a more useful approach. Radicicol and geldanamycin could both maintain chaperone induction for at least 3 weeks and alter the detergent soluble properties of polyQ aggregates over this time course.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoquinones
  • Brain / metabolism*
  • Brain / pathology
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Crosses, Genetic
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology
  • Lactams, Macrocyclic
  • Lactones / pharmacology
  • Macrolides
  • Mice
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Peptides / metabolism*
  • Quinones / pharmacology
  • RNA, Messenger / biosynthesis


  • Benzoquinones
  • Enzyme Inhibitors
  • Lactams, Macrocyclic
  • Lactones
  • Macrolides
  • Molecular Chaperones
  • Peptides
  • Quinones
  • RNA, Messenger
  • polyglutamine
  • monorden
  • geldanamycin