A molecular switch controls interspecies prion disease transmission in mice
Christina J. Sigurdson, … , Kurt Wüthrich, Adriano Aguzzi
Christina J. Sigurdson, … , Kurt Wüthrich, Adriano Aguzzi
Published June 14, 2010
Citation Information: J Clin Invest. 2010;120(7):2590-2599. https://doi.org/10.1172/JCI42051.
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Research Article Neuroscience

A molecular switch controls interspecies prion disease transmission in mice

Abstract

Transmissible spongiform encephalopathies are lethal neurodegenerative disorders that present with aggregated forms of the cellular prion protein (PrPC), which are known as PrPSc. Prions from different species vary considerably in their transmissibility to xenogeneic hosts. The variable transmission barriers depend on sequence differences between incoming PrPSc and host PrPC and additionally, on strain-dependent conformational properties of PrPSc. The β2-α2 loop region within PrPC varies substantially between species, with its structure being influenced by the residue types in the 2 amino acid sequence positions 170 (most commonly S or N) and 174 (N or T). In this study, we inoculated prions from 5 different species into transgenic mice expressing either disordered-loop or rigid-loop PrPC variants. Similar β2-α2 loop structures correlated with efficient transmission, whereas dissimilar loops correlated with strong transmission barriers. We then classified literature data on cross-species transmission according to the 170S/N polymorphism. Transmission barriers were generally low between species with the same amino acid residue in position 170 and high between those with different residues. These findings point to a triggering role of the local β2-α2 loop structure for prion transmissibility between different species.

Authors

Christina J. Sigurdson, K. Peter R. Nilsson, Simone Hornemann, Giuseppe Manco, Natalia Fernández-Borges, Petra Schwarz, Joaquín Castilla, Kurt Wüthrich, Adriano Aguzzi

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Figure 2

The RL induces a species barrier for RML infection.

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The RL induces a species barrier for RML infection. (A) Schematic illust...
(A) Schematic illustrating the passages of RML mouse-adapted scrapie into the tga20 and tg1020 mice. The labels i–iv indicate the inoculation groups labeled in the survival curves in B. (B) RML induces prion disease in tg1020 mice after a prolonged, highly variable ip (blue line). In contrast, tga20 mice infected with RML have a short, invariable ip (red line). WT mice infected with RML are shown for comparison. RL-RML1 leads to a shortened, more consistent ip in tg1020 mice but a prolonged, variable ip in tga20 mice, indicative of a species barrier effect. (C) Diffuse PrPSc staining occurs in the brain after RML infection of tg1020 and tga20 mice. Only aggregates in tg1020 mice were positive with PTAA staining (arrows). Scale bars: 400 μm (RML); 50 μm (PTAA). (D) Passage of the RL-RML resulted in abundant PrPSc deposits in tg1020 mice but very little PrPSc stain in tga20 mice, as shown by PrP immunohistochemistry (anti-PrP monoclonal antibody, SAF84). Histoblots of RL-RML also depict widespread distribution of PK-resistant PrP (PK concentration, 100 μg/ml). Scale bars: 200 μm (RL-RML); 500 μm (histoblot). (E) The correlation diagram of emission intensity of PTAA-bound PrP aggregates at wavelength ratios 531 nm/642 nm (R531/642) and 531 nm/the emission maxima (R531/Emax) shows the high variability of the RL-RML1 in tg1020 mice. M-NS, mouse-adapted sheep scrapie. RL-RML1 is a prion strain derived from RL mice infected with RML. (F) Westerns blots of the RL-RML1 passage show homogeneous levels of PrPSc in tg1020 mice but heterogenous levels in tga20 mice.