A molecular switch controls interspecies prion disease transmission in mice

作者：Sigurdson Christina J; Nilsson K Peter R; Hornemann Simone; Manco Giuseppe; Fernandez Borges Natalia; Schwarz Petra; Castilla Joaquin; Wuethrich Kurt; Aguzzi Adriano^*

来源：Journal of Clinical Investigation, 2010, 120(7): 2590-2599.

DOI：10.1172/JCI42051

Transmissible spongiform encephalopathies are lethal neurodegenerative disorders that present with aggregated forms of the cellular prion protein (PrP(C)), which are known as PrP(Sc). Prions from different species vary considerably in their transmissibility to xenogeneic hosts. The variable transmission barriers depend on sequence differences between incoming PrP(Sc) and host PrP(C) and additionally, on strain-dependent conformational properties of PrP(Sc). The beta(2)-alpha(2) loop region within PrP(C) 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 PrP(C) variants. Similar beta 2-alpha 2 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 beta 2-alpha 2 loop structure for prion transmissibility between different species.

• 出版日期2010-7