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

• Published in: Human molecular genetics 2004-07, Vol.13 (13), p.1389-1405
• Main Authors: Hay, David G., Sathasivam, Kirupa, Tobaben, Sönke, Stahl, Bernd, Marber, Michael, Mestril, Ruben, Mahal, Amarbirpal, Smith, Donna L., Woodman, Ben, Bates, Gillian P.
• Format: Article
• Language: English
• Subjects: Animals; Benzoquinones; Biological and medical sciences; Brain - metabolism; Brain - pathology; Caenorhabditis elegans; Cell Nucleus - metabolism; Cells, Cultured; Crosses, Genetic; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Drosophila melanogaster; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Genetics of eukaryotes. Biological and molecular evolution; Huntington Disease - metabolism; Huntington Disease - pathology; Lactams, Macrocyclic; Lactones - pharmacology; Macrolides; Medical sciences; Mice; Molecular and cellular biology; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Neurology; Peptides - metabolism; Quinones - pharmacology; RNA, Messenger - biosynthesis; Saccharomyces cerevisiae
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddh144

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.