PrPC expression in the peripheral nervous system is a determinant of prionneuroinvasion

Transmissible spongiform encephalopathies are often propagated by extracere bral inoculation. The mechanism of spread from peripheral portals of entry to the central nervous system (neuroinvasion) is complex: while lymphatic o rgans typically show early accumulation of prions, and B-cells and follicul ar dendritic cells are required for efficient neuroinvasion, actual entry i nto the central nervous system occurs probably via peripheral nerves and ma y utilize a PrPC-dependent mechanism. This study shows that transgenic mice overexpressing PrPC undergo rapid and efficient neuroinvasion upon intrane rval and footpad inoculation of prions, These mice exhibited deposition of the pathological isoform of the prion protein (PrPSc) and infectivity in sp ecific portions of the central and peripheral sensory pathways, but almost no splenic PrPSc accumulation, In contrast, wild-type mice always accumulat ed splenic PrPSc, and had widespread deposition of PrPSc throughout the cen tral nervous system even when prions were injected directly into the sciati c nerve, These results indicate that a lympho-neural sequence of spread occ urs in wild-type mice even upon intranerval inoculation, while overexpressi on of PrPC leads to substantial predilection of intranerval over lymphoreti cular spread. The rate of transport of infectivity in peripheral nerves was ca. 0.7 mm per day, and prion infectivity titres of sciatic nerves were mu ch higher in tga20 than in wild-type mice, suggesting that overexpression o f PrPC modulates the capacity for intranerval transport.