Human Molecular Genetics Advance Access published online on April 28, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh144
© 2004 by Oxford University Press
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1 Medical and Molecular Genetics, GKT School of Medicine, King's College London SE1 9RT, UK; CRUK Tumour Cytokine Biology Group, Wolfson Digestive Disease Centre, University Hospital, Nottingham NG7 2UH, UK
* To whom correspondence should be addressed. E-mail: gillian.bates{at}genetics.kcl.ac.uk.
The manipulation of chaperone levels has been shown to inhibit aggregation and/or rescue cell death in cell culture, S. cerevisiae, C. elegans and D. melanogaster models of Huntington's disease (HD) and other polyglutamine disorders. We show here that a progressive decrease in Hdj1, Hdj2, Hsp70,
Article
Progressive decrease in chaperone protein levels in a mouse model of huntington's disease and induction of stress proteins as a therapeutic approach
2 Medical and Molecular Genetics, GKT School of Medicine, King's College London SE1 9RT, UK
3 Molecular Design Limited, 60486 Frankfurt, Germany
4 Institute for Molecular Biology and Cancer Research, University of Marburg, 35033 Marburg, Germany
5 Department of Cardiology, GKT School of Medicine, King's College London SE1 7EH, UK
6 Department of Physiology, Loyola University, Maywood, IL 60153, USA
7 Medical and Molecular Genetics, GKT School of Medicine, King's College London SE1 9RT, UK; MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London W12 0NN, UK
8 Medical and Molecular Genetics, GKT School of Medicine, King's College London SE1 9RT, UK; Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
9 Medical and Molecular Genetics, GKT School of Medicine, King's College London, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT
Abstract 
SGT and 
SGT brain levels likely contribute to disease pathogenesis in the R6/2 mouse model of HD. Despite a predominantly extranuclear location, Hdj1, Hdj2, Hsc70, SGT and SGT were found to co-localise 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 one 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 three weeks, and altered the detergent soluble properties of polyglutamine aggregates over this time course.
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