NR ARNJ
AU Masel,J.; Genoud,N.; Aguzzi,A.
TI Efficient inhibition of prion replication by PrP-Fc(2) suggests that the prion is a PrPsc oligomer
QU Journal of Molecular Biology 2005 Feb 4; 345(5): 1243-51
PT journal article
AB Soluble dimeric prion protein (PrP-Fc(2)) binds to the disease-associated prion protein PrPsc, and inhibits prion replication when expressed in transgenic mice. Prion inhibition is effective even if PrP-Fc(2) is expressed at low levels, suggesting that its affinity for PrPsc is higher than that of monomeric PrPc. Here, we model prion accumulation as an exponential replication cycle of prion elongation and breakage. The exponential growth rate corresponding to this cycle is reflected in the incubation period of the disease. We use a mathematical model to calculate the exponential growth rate, and fit the model to in vivo data on prion incubation times corresponding to different levels of PrPc and PrP-Fc(2). We find an excellent fit of the model to the data. Surprisingly, targeting of PrPsc can be effective at concentrations of PrP-Fc(2) lower than that of PrPc, even if PrP-Fc(2) and PrPc have the same affinity for PrPsc. The best fit of our model to data predicts that the replicative prion consists of PrPsc oligomers with a mean size of four to 15 units.
MH Animals; Dimerization; Mice; Models, Biological; PrPsc Proteins/*chemistry/*metabolism; Prions/antagonists & inhibitors/chemistry/*metabolism/*pharmacology; Protein Structure, Quaternary; Research Support, Non-U.S. Gov't
AD Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, AZ 85721, USA. masel@u.arizona.edu
SP englisch
PO England