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

The manipulation of chaperone levels has been shown to inhibit aggregation and/or rescue cell death inSaccharomyces cerevisiae, Caenorhabditis elegans,Drosophila melanogaster and cell culture models ofHuntington’s disease (HD) and other polyglutamine (polyQ) disorders. We show here that a progressivedecrease in Hdj1, Hdj2, Hsp70, aSGT and bSGT brain levels likely contributes to disease pathogenesis inthe R6/2 mouse model of HD. Despite a predominantly extranuclear location, Hdj1, Hdj2, Hsc70, aSGT andbSGT were found to co-localize with nuclear but not withextranuclear aggregates. Quantification of Hdj1and aSGT mRNA levels showed that these do not change and therefore the decrease in protein levels maybe a consequence of their sequestration to aggregates, or an increase in protein turnover, possibly as a con-sequence of their relocation to the nucleus. We have used genetic and pharmacological approaches toassess the therapeutic potential of chaperone manipulation. Ubiquitous overexpression of Hsp70 in theR6/2 mouse (as a result of crossing to Hsp70 transgenics) delays aggregate formation by 1 week, has noeffect 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 shockresponse might be a more useful approach. Radicicol and geldanamycin could both maintain chaperoneinduction for at least 3 weeks and alter the detergent soluble properties of polyQ aggregates over thistime course.INTRODUCTIONNine inherited late-onset neurodegenerative disorders, includingHuntington’s disease (HD), dentatorubral pallidoluysianatrophy (DRPLA), the spinocerebellar ataxias (SCA) 1, 2, 3,6, 7 and 17, and spinal and bulbar muscular atrophy (SBMA)are caused by a CAG/polyglutamine (polyQ) repeat expansion(1). In all cases the neuropathology of these diseases is charac-terized by the presence of nuclear, and in some cases extra-nuclear, aggregates that are immunoreactive for the mutantprotein and for ubiquitin. Although it is likely that themisfolding and accumulation of mutant polyQ is central tothe pathogenesis of these diseases, the structures of the inter-mediates involved in aggregate formation, the stage at whichHuman Molecular Genetics, Vol. 13, No. 13