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 1

Amino acid sequence and 3-dimensional structure comparisons for WT mouse PrPC (Prnp a), mouse RL-PrPC, and for WT-PrPC of 4 additional mammalian species.

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Amino acid sequence and 3-dimensional structure comparisons for WT mouse...
(A) PrP amino acid sequence of PrP from mouse (mPrP; Mus musculus, AAA39997) and the RL variant thereof and Syrian hamster (shPrP; Mesocricetus auratus, AAA37091), elk (ePrP; Cervus elaphus nelsoni, AAB94788), sheep (ovPrP; Ovis aries, ABC61639), and cattle PrP (bPrP; Bos taurus, ABU97893). For mouse PrPC, the residues 23–231 are shown. For the RL variant and the other species, the only amino acids indicated are those that differ from the mouse PrP sequence, with identical amino acids indicated by dots and deletions indicated by dashes. The shaded region indicates the β2-α2 loop region, and the “X” in the ovine indicates a polymorphic residue position (Q/R). At the top, the regular secondary structure elements are shown. (B) Backbone superpositions of residues 125–228 of RL-PrPC (gray) with mouse PrPC (dark blue), Syrian hamster PrPC (light blue), elk PrPC (yellow), sheep PrPC (pink), and cattle PrPC (purple) (adapted from refs. 44–47, 51). A larger view of the region in the red box is shown in C. (C) Backbone fold of residues 165–172 in RL-PrPC, mouse PrPC, Syrian hamster PrPC, elk PrPC, sheep PrPC, and cattle PrPC. The radius of the cylindrical rods representing the polypeptide chains is proportional to the mean global backbone displacement for residues from 20 conformers used to represent the NMR structures. The same color code is used as in B.