8 Knockouts, Knockins, Transgenics, and Transplants in Prion Research

Abstract

The “protein only” hypothesis proposes that the prion is a conformational isoform of the normal host protein PrP^C and that the abnormal conformer, when introduced into the organism, causes the conversion of PrP^C into a likeness of itself. PrP^C is encoded by a single-copy gene (Basler et al. 1986) located on chromosome 2 in mouse (Prnp) and on chromosome 20 (PRNP) in humans. A PrP gene has been found in all vertebrates examined (Wopfner et al. 1999), including birds (Wopfner et al. 1999), amphibians (Strumbo et al. 2001), and reptiles (Simonic et al. 2000); moreover, a PrP-like gene was identified in fugu fish (Suzuki et al. 2002).

Maturation of the primary translation product results in removal of an amino-terminal signal sequence of 22 amino acids, replacement of 23 amino acids at the carboxyl terminus by a glycosylphosphatidylinositol (GPI) residue, and glycosylation at two asparagine residues. Mature PrP^C comprises a highly flexible amino-terminal half, made up of octapeptide repeats, and a globular domain consisting of three α-helices, one short antiparallel β-sheet, and a single disulfide bond (Riek et al. 1996Riek et al. 1997; Donne et al. 1997). Cu⁺⁺ binds both to the octapeptide region and to histidines 96 and 111 of the PrP flexible tail (Sulkowski 1992; Hornshaw et al. 1995; Brown et al. 1997b; Jackson et al. 2001). PrP^C is anchored to the outer surface of the cell membrane, in cholesterol-rich microdomains or caveolae (Vey et al. 1996; Naslavsky et al. 1997), and undergoes endocytosis and recycling (Shyng et al. 1993, 1995;...