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First posted online 18 August 2000 ARTICLE ABSTRACT
Rec 16 May 2000; Acc 3 August 2000 DOI: 10.1099/vir.0.17152-0

PrPC expression in the peripheral nervous system is a determinant of prion neuroinvasion

Markus Glatzel and Adriano Aguzzi

Institute of Neuropathology, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland

Transmissible spongiform encephalopathies are often propagated by extracerebral inoculation. The mechanism of spread from peripheral portals of entry to the central nervous system (neuroinvasion) is complex: while lymphatic organs typically show early accumulation of prions, and B-cells and follicular dendritic cells are required for efficient neuroinvasion, actual entry into the central nervous system occurs probably via peripheral nerves and may utilize a PrPC-dependent mechanism. This study shows that transgenic mice overexpressing PrPC undergo rapid and efficient neuroinvasion upon intranerval and footpad inoculation of prions. These mice exhibited deposition of the pathological isoform of the prion protein (PrPSc) and infectivity in specific portions of the central and peripheral sensory pathways, but almost no splenic PrPSc accumulation. In contrast, wild-type mice always accumulated splenic PrPSc, and had widespread deposition of PrPSc throughout the central nervous system even when prions were injected directly into the sciatic nerve. These results indicate that a lympho-neural sequence of spread occurs in wild-type mice even upon intranerval inoculation, while overexpression of PrPC leads to substantial predilection of intranerval over lymphoreticular 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 much higher in tga20 than in wild-type mice, suggesting that overexpression of PrPC modulates the capacity for intranerval transport.

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This article is now available in the November 2000 print issue of JGV (vol. 81, 2813–2821). The complete issue of the journal may be seen in electronic form on JGV Online.