A TRANSMEMBRANE FORM OF THE PRION PROTEIN IN NEURODEGENERATIVE DISEASE

At the endoplasmic reticulum membrane, the prion protein (PrP) can be synthesized in several topological forms. The role of these different forms was explored with transgenic mice expressing PrP mutations that alter the relative ratios of the topological forms, Expression of a pa rticular transmembrane form (termed (PrP)-Pr-Ctm) produced neurodegene rative changes in mice similar to those of some genetic prion diseases , Brains from these mice contained (PrP)-Pr-Cim but not PrPSc, the PrP isoform responsible for transmission of prion diseases, Furthermore, in one heritable prion disease of humans, brain tissue contained (PrP) -Pr-Ctm but not PrPSc, Thus, aberrant regulation of protein biogenesis and topology at the endoplasmic reticulum can result in neurodegenera tion.