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

Annie Sittler, Rudi Lurz, Gerhild Lueder, Josef Priller, Manajit K. Hayer-Hartl, F. Ulrich Hartl, Hans Lehrach, Erich E. Wanker

Research output: Contribution to journalArticlepeer-review

385 Scopus citations

Abstract

Huntington's disease (HD) is a progressive neuro-degenerative 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)1307-1315
Number of pages9
JournalHuman Molecular Genetics
Volume10
Issue number12
DOIs
StatePublished - 1 Jun 2001
Externally publishedYes

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