Stabilization of a prion strain of synthetic origin requires multiple serial passages

Abstract

Transmission of prions to a new host is frequently accompanied by strain adaptation, a phenomenon that involves reduction of the incubation period, a change in neuropathological features and, sometimes, tissue tropism. Here we show that a strain of synthetic origin (SSLOW), although serially transmitted within the same species, displayed the key attributes of the strain adaptation process. At least four serial passages were required to stabilize the strain-specific SSLOW phenotype. The biological titration of SSLOW revealed a correlation between clinical signs and accumulation of PrPSc in brains of animals inoculated with high doses (10-1-10-5 diluted brain material), but dissociation between the two processes at low dose inocula (10-6-10-8 diluted brain material). At low doses, several asymptomatic animals harbored large amounts of PrPSc comparable with those seen in the brains of terminally ill animals, whereas one clinically ill animal had very little, if any, PrPSc. In summary, the current study illustrates that the phenomenon of prion strain adaptation is more common than generally thought and could be observed upon serial transmission without changing the host species. When PrPSc is seeded by recombinant PrP structures different from that of authentic PrPSc, PrPSc properties continued to evolve for as long as four serial passages.