THE ABNORMAL ISOFORM OF THE PRION PROTEIN ACCUMULATES IN LATE-ENDOSOME-LIKE ORGANELLES IN SCRAPIE-INFECTED MOUSE-BRAIN

The prion encephalopathies are characterized by accumulation in the br ain of the abnormal form PrPsc of a normal host gene product PrPc. The mechanism and site of formation of PrPsc from PrPc are currently unkn own. In this study, ME7 scrapie-infected mouse brain was used to show, both biochemically and by double-labelled immunogold electron microsc opy, that proteinase K-resistant PrPsc is enriched in subcellular stru ctures which contain the cation-independent mannose 6-phosphate recept or, ubiquitin-protein conjugates, beta-glucuronidase, and cathepsin B, termed late endosome-like organelles. The glycosylinositol phospholip id membrane-anchored PrPc will enter such compartments for normal degr adation and the organelles may therefore act as chambers for the conve rsion of PrPc into infectious PrPsc in this murine model of scrapie.