Chemical Induction of Misfolded Prion Protein Conformers in Cell Culture

摘要

Prion-infected cells accumulate a heterogeneous population of aberrantly folded PrP conformers, including the disease-causing isoform (PrP^Sc). We found that specific chemicals can modulate the levels of various PrP conformers in cultured cells. Positively charged polyamidoamines (dendrimers) eliminated protease-resistant (r) PrP^Sc from prion-infected cells and induced the formation of insoluble, protease-sensitive PrP aggregates (designated PrP^A). Larger, positively charged polyamidoamines more efficaciously induced the formation of PrP^A and cleared rPrP^Sc, whereas negatively charged polyamidoamines neither induced PrP^A nor cleared rPrP^Sc. Although the biochemical properties of PrP^A were shown to be similar to protease-sensitive (s) PrP^Sc, bioassays of PrP^A indicated that it is not infectious. Our studies argue that PrP^A represents an aggregated PrP species that is off-pathway relative to the formation of rPrP^Sc. It remains to be established whether the formation of PrP^A inhibits the formation of rPrP^Sc by sequestering PrP^C in the form of benign, insoluble aggregates.