Journal Article

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 and Erich E. Wanker

in Human Molecular Genetics

Volume 10, issue 12, pages 1307-1315
Published in print June 2001 | ISSN: 0964-6906
Published online June 2001 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/10.12.1307
Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease

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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.

Journal Article.  5267 words.  Illustrated.

Subjects: Genetics and Genomics

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