Intracellular re-routing of prion protein prevents propagation of PrPSc and delays onset of prion disease

Prion diseases are fatal and transmissible neurodegenerative disorders link ed to an aberrant conformation of the cellular prion protein (PrPc). We sho w that the chemical compound Suramin induced aggregation of PrP in a post-E R/Golgi compartment and prevented further trafficking of PrPc to the outer leaflet of the plasma membrane. Instead, misfolded PrP was efficiently re-r outed to acidic compartments for intracellular degradation. In contrast to PrPc in prion-infected cells, PrP aggregates formed in the presence of Sura min did not accumulate, were entirely sensitive to proteolytic digestion, h ad distinct biophysical properties, and were not infectious. The prophylact ic potential of Suramin-induced intracellular re-routing was tested in mice . After intraperitoneal infection with scrapie prions, peripheral applicati on of Suramin around the time of inoculation significantly delayed onset of prion disease. Our data reveal a novel quality control mechanism for misfo lded PrP isoforms and introduce a new molecular mechanism for anti-prion co mpounds.