Human Molecular Genetics Advance Access originally published online on April 28, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 13 1389-1405
DOI: 10.1093/hmg/ddh144
Human Molecular Genetics, Vol. 13, No. 13 © Oxford University Press 2004; all rights reserved
Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach
1Medical and Molecular Genetics, GKT School of Medicine, King's College, London SE1 9RT, UK, 2Molecular Design Limited, 60486 Frankfurt, Germany, 3Institute for Molecular Biology and Cancer Research, University of Marburg, 35033 Marburg, Germany, 4Department of Cardiology, GKT School of Medicine, King's College, London SE1 7EH, UK and 5Department of Physiology, Loyola University, Maywood, IL 60153, USA
Received March 24, 2004; Accepted April 21, 2004
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, 
SGT and ßSGT brain levels likely contributes to disease pathogenesis in the R6/2 mouse model of HD. Despite a predominantly extranuclear location, Hdj1, Hdj2, Hsc70, SGT and ßSGT were found to co-localize with nuclear but not with extranuclear aggregates. Quantification of Hdj1 and SGT 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.
* To whom correspondence should be addressed at: Medical and Molecular Genetics, GKT School of Medicine, King's College London, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK. Tel: +44 2071883722; Fax: +44 2071883727; Email: gillian.bates{at}genetics.kcl.ac.uk
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