Figure 6. Diagrammatic representation of kinetics of prion propagation and toxicity.

Prion replication (dotted lines) is exponential in phase 1 until a limiting titre of prions (infectivity plateau) is attained independent of PrP^C expression level. Plateau length (phase 2) is inversely proportional to PrP^C expression level3. During phase 1, total PrP levels do not significantly change from the starting PrP^C level before infection (Fig. 1). PK-sensitive disease-related PrP is total PrP minus starting PrP^C level (by definition zero in all three mouse lines before infection) and classical PrP^Sc. At the phase transition, PK-sensitive disease-related PrP isoforms begin to accumulate (solid lines). The rise of PK-sensitive disease-related PrP appears linear and approximately proportional to mouse PrP^C expression level (Figs 1 and 3). Onset of clinical disease occurs when a critical level of toxic species is reached, which is closely similar in each mouse line.