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 of several monomeric PrP^Sc molecules are mounted into a highly ordered seed, can further monomeric PrP^Sc and eventually aggregates of amyloid be recruited. 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 N- and C-terminal signal sequences. Upon reaching its destination on the cell surface, an N-terminal secretory signal peptide of 22 amino acids is cleaved from the 254 amino acid PrP^C precursor protein. Twenty-three C-terminal residues are also processed during addition of the glycosyl phosphatidylinositol (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 structures. 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.

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 digest with proteinase K. Different inocula result in specific mobilities of the three PrP bands as well as different predominance of certain bands (middle panel). These characteristic patterns can be retained, or changed to other predictable patterns after passage in wild-type mice (upper panel) or humanized mice (PrP-deficient mice bearing a human PrP transgene, lower panel). On the basis of 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. By contrast, all cases of nvCJD displayed a novel pattern, designated a type-4 pattern.

Figure 4. Characteristic neuropathologic features of transmissible spongiform encephalopathies. Gray matter of the brain of a CJD patient stained with hematoxylin and eosin (H & E) displaying the characteristic spongiform, vacuole-like morphology (left). Activation and proliferation of reactive, swollen astrocytes is visualized by staining with antibodies against glial fibrillary acidic protein (GFAP, brown color, middle). Immunohistochemical staining using anti-PrP antibodies representing prion protein deposits (brown color, right).