Chemical induction of misfolded prion protein conformers in cell culture

J Biol Chem. 2010 Apr 2;285(14):10415-23. doi: 10.1074/jbc.M109.045112. Epub 2009 Dec 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Brain / drug effects
  • Brain / metabolism
  • Chromatography, Gel
  • Dendrimers / pharmacology*
  • Dimerization
  • Endopeptidases / metabolism
  • Mice
  • Mice, Transgenic
  • Neuroblastoma / drug therapy
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Nylons / pharmacology*
  • PrPC Proteins / chemistry*
  • PrPC Proteins / metabolism
  • PrPSc Proteins / chemistry*
  • PrPSc Proteins / metabolism
  • Protein Conformation
  • Protein Folding / drug effects*
  • Protein Isoforms
  • Protein Multimerization / drug effects*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured


  • Dendrimers
  • Nylons
  • PAMAM-G4
  • PrPC Proteins
  • PrPSc Proteins
  • Protein Isoforms
  • RNA, Messenger
  • Endopeptidases