Evidence for synthesis of scrapie prion proteins in the endocytic pathway

David R. Borchelt, Albert Taraboulos, Stanley B. Prusiner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

460 Scopus citations

Abstract

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°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.

Original languageEnglish
Pages (from-to)16188-16199
Number of pages12
JournalJournal of Biological Chemistry
Volume267
Issue number23
StatePublished - 15 Aug 1992
Externally publishedYes

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