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

• Published in: Human molecular genetics 2001-06, Vol.10 (12), p.1307-1315
• Main Authors: SITTLER, Annie, LURZ, Rudi, LUEDER, Gerhild, PRILLER, Josef, HAYER-HARTL, Manajit K, HARTL, F. Ulrich, LEHRACH, Hans, WANKER, Erich E
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Benzoquinones; Biological and medical sciences; COS Cells; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Exons; Geldanamycin; Heat-Shock Proteins - metabolism; Heat-Shock Response - drug effects; HSP40 Heat-Shock Proteins; Hsp40 protein; HSP70 Heat-Shock Proteins - metabolism; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Huntingtin Protein; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington Disease - immunology; Huntington Disease - metabolism; Lactams, Macrocyclic; Medical sciences; Molecular Sequence Data; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Peptides - metabolism; Quinones - pharmacology
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/10.12.1307

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.