A WILD-TYPE PRION PROTEIN DOES NOT ACQUIRE PROPERTIES OF THE SCRAPIE ISOFORM WHEN COEXPRESSED WITH A MUTANT PRION PROTEIN IN CULTURED-CELLS

Inherited prion diseases are linked to autosomal dominant mutations in the gene that encodes the prion protein (PrP). These mutations are th ought to induce PrP to undergo a conformational alteration that conver ts it to a pathogenic form designated PrPSc. In patients who are heter ozygous for PrP mutations, the protein encoded by the wild-type allele might influence the conversion of the mutant protein to the PrPSc sta te, and might itself be converted into PrPSc. To test these possibilit ies, we have constructed stably transfected lines of CHO cells that ex press both wild-type mouse PrP and mouse PrP carrying an insertional m utation that is homologous to one associated with familial Creutzfeldt -Jakob disease. We find that wild-type PrP in these cells does not acq uire any of four different biochemical properties characteristic of Pr PSc that we have previously documented in mutant PrPs expressed in CHO cells. We also observe that conversion of the mutant protein to a PrP Sc-like state is not impaired by coexpression of the wild-type protein . These results are consistent with the idea that sequence homology be tween PrP molecules has an important influence on PrPSc generation, an d they provide insight into the metabolism of PrP in patients who are heterozygous at the PrP locus. (C) 1997 Elsevier Science B.V.