Prion replication, models

Fig. 5 Models of prion replication, (a) The template assistance model predicts that a PrPSo monomer is more stable than PrPc, but is kinetically inaccessible. In the rare event that a PrPSo monomer is created spontaneously (or provided exogenously), it can template the misfolding of another PrPc molecule by direct interaction. The dashed line shows that the newly created PrPSc monomer can act as another seed to formation of PrPSc. (b) The nucleation polymerization model predicts that barrier to prion protein conversion is the formation of a nucleus in which the protein adopts a PrPSo-like structure. The formation of such a low order aggregate is not favored however, once it has formed, polymerization from a pool of PrPc molecules can take place efficiently. Fragmentation of the polymer increases the number of ends for the recruitment of PrPc monomers...

Fig. 3. Model of the life cycle of prions. PrP is synthesized in the rough endoplas-matic reticulum (ER), and after passing through the secretory pathway including the Golgi and secretory vesicles, reaches the surface of a PrP infectable cell where it is anchored via a glycosylphosphatidyl inositol (GPI) moiety. Endocytosis of PrP and possibly PrP via clathrin coated vesicles could be mediated by the 37 kDa laminin receptor precursor (LRP). The uptake of the infectious agent could also be LRP independent. The conversion of the internalized PrP to PrP is thought to take place in the endo-somes, lysosomes, or endolysosomes. Molecular chaperones could be involved in this conversion process. PrP replication and aggregation can occur in neuronal cells of the brain but also in the cells constituting the lymphoreticular system. Alternatively, endocytosis and conversion of PrP into PrP could happen in caveolae-like domains (CLDs).

Which mechanism could induce such a dramatic change of the 3D structure of a protein How could the a —> p conversion of PrP into PrP " account for the pathogenic properties of this protein In 1967 (25 years before Prusiner invented the term prion), a remarkably inspired mathematician, J. S. Griffith, proposed a simple but prophetic model of a disease caused by the replication of an infectious protein. One of his hypothesis was that the brain expressed a "normal" form of the protein, whereas the infectious particle contained an "abnormal" form of the same protein. The abnormal form of the protein was then supposed to bind to the normal brain protein and to convert it into a disease-causing protein. This simple mechanism... 

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