Models of PrP-res Formation

Before considering the experimental ohservations relating to the mechanism of PrP-res formation, it may be helpful to have prevalent theoretical models of PrP-res formation in mind. A wide variety of mechanisms and permutations of mechanisms have been proposed for PrP-res formation. Two that are most commonly considered are the heterodimer model (Griffith, 1967 Bolton and Bendheim, 1988 Prusiner, 

1998) and the nucleation (seed)-dependent polymerization models (Griffith, 1967 Gadjusek, 1988 Jarrett and Lansbury, Jr., 1993 Lans-bury, Jr. and Caughey, 1995) (Pig. 3). In its simplest rendition, the heterodimer model posits that PrP-res exists in a stable monomeric state that can bind PrP, forming a heterodimer, and catalyze a conformational change in PrP to form a homodimer of PrP-res. The PrP-res homodimer then splits apart to give two PrP-res monomers. Punda-mental aspects of this model are that PrP-res is more stable thermody- 

In the nucleated polymerization type of model, oligomerization/polymerization of PrP is necessary to stabilize PrP-res sufficiently to allow its accumulation to biologically relevant levels. Spontaneous formation of nuclei or seeds of PrP-res is rare because of the weakness of monovalent interactions between PrP molecules and/or the rarity of the conformers that polymerize. However, once formed, oligomeric or polymeric seeds are stabilized by multivalent interactions (Jarrett and Lansbury,Jr., 1993). 

In their various permutations, the two types of models can overlap. For instance, autocatalysis (or templating) of the conformational change in PrP by PrP-res may be a feature of either the heterodimer or nucleated polymerization models (Fig. 3). However, the nucleated polymerization could also occur if PrP rapidly interchanges between high a-helix and 

In familial and sporadic human TSEs, formation of an initial template or seed might be a spontaneous and stochastic event that can be potentiated by specific PrP mutations (Jarrett and Lansbury, Jr., 1993 Lansbury, Jr. and Caughey, 1995 Prusiner, 1998). In TSE diseases of infectious origin, transmission might be explained by acquisition of preformed PrP-res templates/seeds. Nonetheless, until the TSE infectious agent is fully understood, it seems prudent to remain open to the possibility that another type of agent, with or without a PrP component, is responsible for TSE transmission and the instigation of PrP-res formation in infected hosts. 

---

The precise mechanism of tfie conversion reaction is not clear. However, a variety of observations warrant consideration in evaluating mechanistic models of PrP-res formation. The reaction is dependent on time and the concentrations of input PrP-res and PrP-sen (Caughey et al, 1995), although dependence on these parameters can be complex and condition-dependent (Caughey et al., 1995 Horiuchi et al,... 

Parchi et al, 1996), sheep (Kascsak et al, 1985 Kascsak et al, 1986), and hamsters (Bessen and Marsh, 1994). At least 20 strains have heen extensively characterized and studied in experimental mouse models of scrapie (Bruce, 1996). It is especially challenging to explain TSE strains in terms of PrP-res formation because multiple strains have been described in species with one PrP genotype. Because the TSE appear to be a disease of protein folding, the answer may reside not in the PrP amino acid sequence but rather in the conformation of the protein. 

Fig. 3. Mechanistic models for formation of PrP-res from PrP. In the heterodimer and autocatalytic nucleated polyerization models, the conformational conversion of PrP to PrP-res is rare unless catalyzed by contact with monomeric or polymeric PrP-res, respectively. In the noncatalytic nucleated polymerization model, the conformational interchange is rapid, but the PrP-res conformer is poorly populated unless stabilized by binding to a preformed, stable PrP-res polymer. See text for further explanation. The wavy lines in the PrP-sen and PrP-res structures designate the flexibly disordered portion of the structure (usually N-terminal residues 23 to - 89), which remains sensitive to PK after conversion to PrP-res.

---