INSOLUBLE WILD-TYPE AND PROTEASE-RESISTANT MUTANT PRION PROTEIN IN BRAINS OF PATIENTS WITH INHERITED PRION DISEASE

We studied prion proteins (PrP) in skin and brains of Libyan Jews carr ying the E200K mutation who died of familial Creutzfeldt-Jakob disease (CJD). Unexpectedly, studies with brain showed that PrP molecules enc oded both by the wild-type (wt) and mutant alleles exhibit altered pro perties characteristic of the prion protein associated with prion dise ases (PrPSc). Using monospecific antisera, we found that wtPrP was ins oluble in the brains of three patients who were heterozygous for the E 200K mutation, whereas mutant PrP was both insoluble and protease-resi stant. Our results argue that both wild-type and mutant PrP undergo co nformational changes and are particularly intriguing, because the norm al isoform PrPC is soluble in nondenaturing detergents and is readily digested by proteases, whereas PrPSc is insoluble and resistant to pro teolytic digestion. Our findings indicate that insoluble wtPrP represe nts a conformational intermediate, the first to be identified, within a pathway in which PrPC is converted to PrPSc.