Journal Article

Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach

David G. Hay, Kirupa Sathasivam, Sönke Tobaben, Bernd Stahl, Michael Marber, Ruben Mestril, Amarbirpal Mahal, Donna L. Smith, Ben Woodman and Gillian P. Bates

in Human Molecular Genetics

Volume 13, issue 13, pages 1389-1405
Published in print July 2004 | ISSN: 0964-6906
Published online April 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh144
Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach

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The manipulation of chaperone levels has been shown to inhibit aggregation and/or rescue cell death in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster and cell culture models of Huntington's disease (HD) and other polyglutamine (polyQ) disorders. We show here that a progressive decrease in Hdj1, Hdj2, Hsp70, αSGT and βSGT brain levels likely contributes to disease pathogenesis in the R6/2 mouse model of HD. Despite a predominantly extranuclear location, Hdj1, Hdj2, Hsc70, αSGT and βSGT were found to co-localize with nuclear but not with extranuclear aggregates. Quantification of Hdj1 and αSGT mRNA levels showed that these do not change and therefore the decrease in protein levels may be a consequence of their sequestration to aggregates, or an increase in protein turnover, possibly as a consequence of their relocation to the nucleus. We have used genetic and pharmacological approaches to assess the therapeutic potential of chaperone manipulation. Ubiquitous overexpression of Hsp70 in the R6/2 mouse (as a result of crossing to Hsp70 transgenics) delays aggregate formation by 1 week, has no effect on the detergent solubility of aggregates and does not alter the course of the neurological phenotype. We used an organotypic slice culture assay to show that pharmacological induction of the heat shock response might be a more useful approach. Radicicol and geldanamycin could both maintain chaperone induction for at least 3 weeks and alter the detergent soluble properties of polyQ aggregates over this time course.

Journal Article.  11758 words.  Illustrated.

Subjects: Genetics and Genomics

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