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 thought to induce PrP to undergo a conformational alteration that converts it to a pathogenic form designated PrP(Sc). In patients who are heterozygous for PrP mutations, the protein encoded by the wild-type allele might influence the conversion of the mutant protein to the PrP(Sc) state, and might itself be converted into PrP(Sc). To test these possibilities, we have constructed stably transfected lines of CHO cells that express both wild-type mouse PrP and mouse PrP carrying an insertional mutation that is homologous to one associated with familial Creutzfeldt-Jakob disease. We find that wild-type PrP in these cells does not acquire any of four different biochemical properties characteristic of PrP(Sc) 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 between PrP molecules has an important influence on PrP(Sc) generation, and they provide insight into the metabolism of PrP in patients who are heterozygous at the PrP locus.