Human Molecular Genetics, 2001, Vol. 10, No. 12 1307-1315
© 2001 Oxford University Press
Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease
Max-Planck Institut für Molekulare Genetik, Ihnestrasse 73, D-14195 Berlin, Germany, 1Department of Neurology, Charité, Humboldt-University, Schumannstrasse 20-21, D-10117 Berlin, Germany and 2Max-Planck Institut für Biochemie, Abt. Zelluläre Biochemie, Am Klopferspitz 18A, D-82152 Martinsried, Germany
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.
+ To whom correspondence should be addressed. Tel: +49 30 8413 1351; Fax: +49 30 8413 1128; Email: wanker@molgen.mpg.de
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