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 3

Mule deer CWD infection of tga20 and tg1020 mice.

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Mule deer CWD infection of tga20 and tg1020 mice. (A) A survival cur...
(A) A survival curve of tga20 and tg1020 mice infected with mule deer CWD shows a shorter and less variable ip in tg1020 mice (blue line), which was slightly longer on second passage (referred to as RL-CWD). (B) Similar to deer, CWD-PrPSc aggregates in tg1020 mice on first passage are small, irregular, and noncongophilic (middle panel). Upon second passage, large unicentric, congophilic plaques emerge (RL-CWD, right panel). Cr, Congo red. (C) The first passage of CWD in tg1020 mice (RL-CWD, 1st; black circles) shows a highly consistent emission profile of PTAA-bound PrP aggregates, whereas on second passage (RL-CWD, 2nd; purple diamonds), both the emission ratio from the first passage and a new ratio from the congophilic plaques emerge. Murine-adapted sheep scrapie (green square) and M-CWD (red triangle) in tga20 mice are also shown for comparison. (D) CWD in tg1020 was primarily PK sensitive on the first passage in tg1020 mice. By the second passage, RL-CWD was PK-resistant (lanes 1–3). M-CWD in tg1020 mice showed weakly PK-resistant PrP (lanes 4–6). (E) tg1020 mice inoculated with M-CWD have a slightly longer and more variable ip, as compared with the tga20 mice. (F) PrP aggregates of M-CWD in tg1020 and tga20 mice are similarly dense and congophilic. (G) The PTAA emission ratio of M-CWD inoculated into the tg1020 mice (RL-MCWD, purple diamond) is more closely similar to that of M-CWD in tga20 mice than to that of murine-adapted sheep scrapie in tga20 mice. Scale bars: 50 μm.