Evidence for synthesis of scrapie prion proteins in the endocytic pathway.
Infectious scrapie prions are composed largely, if not entirely, of an abnormal isoform of the prion protein (PrP) which is designated PrPSc. A chromosomal gene encodes both the cellular prion protein (PrPC) as well as PrPSc. Pulse-chase experiments with scrapie-infected cultured cells indicate that PrPSc is formed by a post-translational process. PrP is translated in the endoplasmic reticulum, modified as it passes through the Golgi, and is transported to the cell surface. Release of nascent PrP from the cell surface by phosphatidylinositol-specific phospholipase C or hydrolysis with dispase prevented PrPSc synthesis. At 18 degrees C, the synthesis of PrPSc was inhibited under conditions that other investigators report a blockage of endosomal fusion with lysosomes. Our results suggest that PrPSc synthesis occurs after PrP transits from the cell surface. Whether all of the PrP molecules have an equal likelihood to be converted into PrPSc or only a distinct subset is eligible for conversion remains to be established. Identifying the subcellular compartment(s) of PrPSc synthesis should be of considerable importance in defining the molecular changes that distinguish PrPSc from PrPC.
Borchelt
D R
DR
Department of Neurology, University of California, San Francisco 94143.
Taraboulos
A
A
Prusiner
S B
SB
D000818:Animals; D001345:Autoradiography; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D004705:Endocytosis; D007700:Kinetics; D008715:Methionine / Q000378:metabolism; D008970:Molecular Weight; D018620:PrPSc Proteins; D011328:Prions / Q000096:biosynthesis* / Q000302:isolation & purification / Q000378:metabolism; D013462:Sulfur Radioisotopes; D013696:Temperature
D018620:PrPSc Proteins; D011328:Prions; D013462:Sulfur Radioisotopes; D008715:Methionine