9 Cell Biology of Prions

Abstract

The cell biology of prions has emerged as an important area of investigation. Studies of the biosynthesis of PrP^C and its trafficking through the cell as it is either degraded or transformed into PrP^Sc have yielded a series of unexpected findings.

BIOGENESIS OF PrP ^C
The biosynthesis of PrP^C is similar to that of many secreted glycoproteins. PrP^C is translated from the mRNA in the endoplasmic reticulum (ER) (Caughey et al. 1989; Borchelt et al. 1990). As the Syrian hamster (SHa) PrP polypeptide chains are being elongated, presumably the signal peptide of 22 amino acids at the amino terminus is removed proteolytically, as for other secretory proteins (Basler et al. 1986; Hope et al. 1986; Turk et al. 1988). After assembly of the polypeptide chain is complete, a signal sequence of 23 amino acids is removed from the carboxyl terminus as a glycosyl phosphatidylinositol (GPI) anchor is added to serine at position 231 (Stahl et al. 1987Stahl et al. 1990). In the ER, the remaining 209 residues of the SHaPrP polypeptide contain a disulfide bond and two asparagine-linked CHOs, as well as the GPI anchor attached to the carboxyl terminus through an ethanolamine (Fig. 1).

As PrP^C is transported through the Golgi apparatus, the sugar chains of the asparagine-linked CHOs and GPI anchor are modified. The high mannose cores of the two asparagine-linked sugar chains are remodeled and subsequently sialylated, and the GPI anchor also undergoes sialylation. The sequences of the asparagine-linked sugar chains were determined on fractions of PrP 27–30 purified...