A specific population of abnormal prion protein aggregates is preferentially taken up by cells and disaggregated in a strain-dependent manner.

Prion diseases are characterized by the conversion of the soluble protease-sensitive host-encoded prion protein (PrP(C)) into its aggregated, protease-resistant, and infectious isoform (PrP(Sc)). One of the earliest events occurring in cells following exposure to an exogenous source of prions is the cellular uptake of PrP(Sc). It is unclear how the biochemical properties of PrP(Sc) influence its uptake, although aggregate size is thought to be important. Here we show that for two different strains of mouse prions, one that infects cells (22L) and one that does not (87V), a fraction of PrP(Sc) associated with distinct sedimentation properties is preferentially taken up by the cells. However, while the fraction of PrP(Sc) and the kinetics of uptake were similar for both strains, PrP(Sc) derived from the 87V strain was disaggregated more rapidly than that derived from 22L. The increased rate of PrP(Sc) disaggregation did not correlate with either the conformational or aggregate stability of 87V PrP(Sc), both of which were greater than those of 22L PrP(Sc). Our data suggest that the kinetics of disaggregation of PrP(Sc) following cellular uptake is independent of PrP(Sc) stability but may be dependent upon some component of the PrP(Sc) aggregate other than PrP. Rapid disaggregation of 87V PrP(Sc) by the cell may contribute, at least in part, to the inability of 87V to infect cells in vitro.