Figure 1. Models for the conformational conversion of PrP^C into PrP^Sc. (A) The ‘refolding’, or template assistance, model postulates an interaction between exogenously introduced PrP^Sc and endogenous PrP^C, which is induced to transform itself into further PrP^Sc. A high energy barrier may prevent spontaneous conversion of PrP^C into PrP^Sc. (B) The ‘seeding’, or nucleation-polymerization, model proposes that PrP^C and PrP^Sc are in a reversible thermodynamic equilibrium. Only if several monomeric PrP^Sc molecules are mounted into a highly ordered seed can further monomeric PrP^Sc be recruited and eventually aggregate to amyloid. Within such a crystal-like seed, PrP^Sc becomes stabilized. Fragmentation of PrP^Sc aggregates increases the number of nuclei, which can recruit further PrP^Sc and thus result in apparent replication of the agent.

Figure 2. Posttranslational processing of PrP^C. The coding region of the human PrP gene displaying the amino- and carboxy-terminal signal sequences; the five blue boxes indicate the ‘octa repeats’, sequences of eight amino acids. Upon reaching its destination on the cell surface, an amino-terminal secretory signal peptide of 22 amino acids is cleaved from the 254-amino-acid PrP^C precursor protein. Twenty-three carboxy-terminal residues are also processed during addition of the GPI-anchor to a serine residue at position 231. Upon completion of these modifications, mature PrP^C contains 209 amino acids. PrP^Sc is a modified form of PrP^C. PrP^C and PrP^Sc have an identical amino acid sequence and share the same posttranslational modifications, but differ in their secondary and (presumably) tertiary structure. The physiological isoform PrP^C is protease-sensitive, while the pathological isoform PrP^Sc is partially protease-resistant, displaying a protease-resistant core of PrP^Sc, designated PrP 27-30. GPI, glycosylphosphatidylinositol; CHO, carbohydrate.

Figure 3. Patterns of PrP glycosylation. Representation of the three glycosylated PrP^Sc moieties (non-, mono- and diglycosylated PrP^Sc) in immunoblots of brain extracts after digestion with proteinase K. Different inocula result in specific mobilities of the three PrP bands as well as different predominance of certain bands (B). These characteristic patterns can be retained, or changed to other predictable patterns after passage in wild-type (A) or humanized mice (PrP-deficient mice bearing a human PrP transgene,) (C). Based on the fragment size and the relative abundance of individual bands, three distinct patterns (PrP^Sc types 1–3) were defined for sporadic and iatrogenic CJD cases. In contrast, all cases of vCJD displayed a novel pattern, designated as type 4 pattern.