A Transmembrane Form of the Prion Protein Is Localized in the Golgi Apparatus of Neurons

CtmPrP is a transmembrane version of the prion protein that has been proposed to be a neurotoxic intermediate underlying prion-induced pathogenesis. In previous studies, we found that PrP molecules carrying mutations in the N-terminal signal peptide (L9R) and the transmembrane domain (3AV) were synthesized exclusively in theCtmPrP form in transfected cell lines. To characterize the properties ofCtmPrP in a neuronal setting, we have utilized cerebellar granule neurons cultured from Tg(L9R–3AV) mice that developed a fatal neurodegenerative illness. We found that about half of the L9R-3AV PrP synthesized in these neurons representsCtmPrP, with the rest beingSecPrP, the glycolipid anchored form that does not span the membrane. Both forms contained an uncleaved signal peptide, and they are differentially glycosylated.SecPrP was localized on the surface of neuronal processes. Most surprisingly,CtmPrP was concentrated in the Golgi apparatus, rather in the endoplasmic reticulum as it is in transfected cell lines. Our study is the first to analyze the properties ofCtmPrP in a neuronal context, and our results suggest new hypotheses about how this form may exert its neurotoxic effects.