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

A Specific Population of Abnormal Prion Protein Aggregates Is Preferentially Taken Up by Cells and Disaggregated in a Strain-Dependent Manner