HUNTINGTIN-ENCODED POLYGLUTAMINE EXPANSIONS FORM AMYLOID-LIKE PROTEINAGGREGATES IN-VITRO AND IN-VIVO

The mechanism by which an elongated polyglutamine sequence causes neur odegeneration in Huntington's disease (HD) is unknown. In this study, we show that the proteolytic cleavage of a GST-huntingtin fusion prote in leads to the formation of insoluble high molecular weight protein a ggregates only when the polyglutamine expansion is in the pathogenic r ange. Electron micrographs of these aggregates revealed a fibrillar or ribbon-like morphology, reminiscent of scrapie prions and beta-amyloi d fibrils in Alzheimer's disease. Subcellular fractionation and ultras tructural techniques showed the in vivo presence of these structures i n the brains of mice transgenic for the HD mutation. Our in vitro mode l will aid in an eventual understanding of the molecular pathology of HD and the development of preventative strategies.