title: 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 beta2-alpha2 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 beta2-alpha2 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 beta2-alpha2 loop structure for prion transmissibility between different species.
authors.affiliation: Department of Pathology and Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA. csigurdson@ucsd.edu
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Sigurdson
authors.forename: K Peter R
authors.initials: KP
authors.lastname: Nilsson
authors.forename: Simone
authors.initials: S
authors.lastname: Hornemann
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manco
authors.forename: Natalia
authors.initials: N
authors.lastname: Fernández-Borges
authors.forename: Petra
authors.initials: P
authors.lastname: Schwarz
authors.forename: Joaquín
authors.initials: J
authors.lastname: Castilla
authors.forename: Kurt
authors.initials: K
authors.lastname: Wüthrich
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D051379:Mice; D008822:Mice, Transgenic; D011110:Polymorphism, Genetic; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism / Q000635:transmission; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms
chemical_list: D011328:Prions