A Transmembrane Form of the Prion Protein Contains an Uncleaved Signal Peptide and Is Retained in the Endoplasmic Reticululm

Abstract

Although there is considerable evidence that PrPScis the infectious form of the prion protein, it has recently been proposed that a transmembrane variant calledCtmPrP is the direct cause of prion-associated neurodegeneration. We report here, using a mutant form of PrP that is synthesized exclusively with theCtmPrP topology, thatCtmPrP is retained in the endoplasmic reticulum and is degraded by the proteasome. We also demonstrate thatCtmPrP contains an uncleaved, N-terminal signal peptide as well as a C-terminal glycolipid anchor. These results provide insight into general mechanisms that control the topology of membrane proteins during their synthesis in the endoplasmic reticulum, and they also suggest possible cellular pathways by whichCtmPrP may cause disease.