Prion protein with an E200K mutation displays properties similar to those of the cellular isoform PrPC

Creutzfeldt-Jakob disease (CJD) in Libyan Jews, linked to the E200K mutatio n in PRNP (E200KCJD), is the most prevalent of the inherited prion diseases . As other prion diseases, E200KCJD is characterized by the brain accumulat ion of PrPSc, a pathologic conformational isoform of a normal glycoprotein denominated PrPC. To investigate whether the E200K mutation is enough to de novo confer PrPSc properties to mutant PrP, as suggested by experiments in Chinese hamster ovary cells, we examined the biochemical behavior of E200K PrP in brains and fibroblasts from sporadic as well as homozygous and heter ozygous E200KCJD patients, asymptomatic transgenic mice carrying the E200K mutation, as well as in normal and scrapie-infected mouse neuroblastoma cel ls expressing E200KPrP. E200KPrP was examined for protease sensitivity, sol ubility in detergents, releasibility by phosphoinositol phospholypase-C and localization in cholesterol enriched membrane microdomains (rafts). In all tissues except in brains of CJD patients and ScN2a cells, E200KPrP display ed properties similar to those of PrPC. Our results indicate that the E200K mutation does not automatically convey the properties of PrPSc to new PrP molecules. A conversion process occurs mainly in the prion disease affected brain, suggesting the presence of a tissue-specific or age-dependent facto r, in accord with the late onset nature of inherited CJD.