Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease.
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.
Sittler
A
A
Max-Planck Institut für Molekulare Genetik, Ihnestrasse 73, D-14195 Berlin, Germany.
Lurz
R
R
Lueder
G
G
Priller
J
J
Lehrach
H
H
Hayer-Hartl
M K
MK
Hartl
F U
FU
Wanker
E E
EE
D000595:Amino Acid Sequence; D000818:Animals; D016227:Benzoquinones; D019556:COS Cells; D005091:Exons; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism*; D018869:Heat-Shock Response / Q000187:drug effects*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D047029:Lactams, Macrocyclic; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology*
D016227:Benzoquinones; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C086055:HTT protein, human; D006360:Heat-Shock Proteins; D000071058:Huntingtin Protein; D047029:Lactams, Macrocyclic; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011809:Quinones; C097188:polyglutamine; C001277:geldanamycin