Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease

A Sittler, R Lurz, G Lueder, J Priller, H Lehrach, M K Hayer-Hartl, F U Hartl, E E Wanker

Research output: Contribution to journalArticlepeer-review

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder with no effective treatment. Geldanamycin is a benzoquinone ansamycin that binds to the heat shock protein Hsp90 and activates a heat shock response in mammalian cells. In this study, we show by using a filter retardation assay and immunofluorescence microscopy that treatment of mammalian cells with geldanamycin at nanomolar concentrations induces the expression of Hsp40, Hsp70 and Hsp90 and inhibits HD exon 1 protein aggregation in a dose-dependent manner. Similar results were obtained by overexpression of Hsp70 and Hsp40 in a separate cell culture model of HD. This is the first demonstration that huntingtin protein aggregation in cells can be suppressed by chemical compounds activating a specific heat shock response. These findings may provide the basis for the development of a novel pharmacotherapy for HD and related glutamine repeat disorders.

Original languageEnglish
Pages (from-to)1307-15
Number of pages9
JournalHuman Molecular Genetics
Volume10
Issue number12
Publication statusPublished - 1 Jun 2001

Keywords

  • Amino Acid Sequence
  • Animals
  • Benzoquinones
  • COS Cells
  • Exons
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Heat-Shock Response
  • Huntingtin Protein
  • Huntington Disease
  • Lactams, Macrocyclic
  • Molecular Sequence Data
  • Mutation
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Quinones
  • Journal Article
  • Research Support, Non-U.S. Gov't

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