Branched
polyamines, including
polyamidoamine and
polypropyleneimine (PPI)
dendrimers, are able to purge PrP(Sc), the disease-causing
isoform of the
prion protein, from
scrapie-infected
neuroblastoma (ScN2a) cells in culture (S. Supattapone, H.-O. B. Nguyen, F. E. Cohen, S. B. Prusiner, and M. R. Scott, Proc. Natl. Acad. Sci. USA 96:14529-14534, 1999). We now demonstrate that exposure of ScN2a cells to 3 microg of PPI generation 4.0/ml for 4 weeks not only reduced PrP(Sc) to a level undetectable by Western blot but also eradicated
prion infectivity as determined by a bioassay in mice. Exposure of purified RML
prions to branched
polyamines in vitro disaggregated the
prion rods, reduced the beta-sheet content of PrP 27-30, and rendered PrP 27-30 susceptible to proteolysis. The susceptibility of PrP(Sc) to proteolytic digestion induced by branched
polyamines in vitro was strain dependent. Notably, PrP(Sc) from
bovine spongiform encephalopathy-infected brain was susceptible to PPI-mediated denaturation in vitro, whereas PrP(Sc) from natural sheep
scrapie-infected brain was resistant.
Fluorescein-labeled PPI accumulated specifically in lysosomes, suggesting that branched
polyamines act within this acidic compartment to mediate PrP(Sc) clearance. Branched
polyamines are the first class of compounds shown to cure
prion infection in living cells and may prove useful as therapeutic, disinfecting, and strain-typing
reagents for
prion diseases.