In
prion diseases the endogenous
prion protein (PrPC) is converted into an abnormally folded
isoform, denoted PrPSc, which represents the major component of infectious
scrapie prions. The mechanism of the conversion is largely unknown, but the conversion is thought to occur after PrPC has reached the plasma membrane. Here we show that exogenous administration of the cationic lipopolyamine
DOSPA interfered with the accumulation of PrPSc in
scrapie-infected
neuroblastoma cells. Structural analysis of the compounds tested revealed that inhibition of PrPSc was specific for
lipids with a headgroup composed of the
polyamine spermine and a quarternary
ammonium ion between the headgroup and the lipophilic tail. The cationic lipopolyamine
DOSPA induced the cellular degradation of preexisting PrPSc aggregates within 12 hours and interfered with the de novo synthesis of PrPSc. Biosynthesis of PrPC, or the assembly of
sphingolipid-
cholesterol microdomains (rafts) on the plasma membrane, were not affected by this inhibitor. After removal of
DOSPA and replating into normal medium propagation of PrPSc commenced, although initially at a reduced rate. Incubation of ScN2a cells in free
spermidine had no inhibitory effect on the accumulation of PrPSc. Our results indicate that membrane targeting of a small
polyamine molecule creates a potent inhibitor of PrPSc propagation and offers the possibility to degrade preexisting PrPSc aggregates in living cells.