title: Prion transmission prevented by modifying the β2-α2 loop structure of host PrPC.
abstract: Zoonotic prion transmission was reported after the bovine spongiform encephalopathy (BSE) epidemic, when >200 cases of prion disease in humans were diagnosed as variant Creutzfeldt-Jakob disease. Assessing the risk of cross-species prion transmission remains challenging. We and others have studied how specific amino acid residue differences between species impact prion conversion and have found that the β2-α2 loop region of the mouse prion protein (residues 165-175) markedly influences infection by sheep scrapie, BSE, mouse-adapted scrapie, deer chronic wasting disease, and hamster-adapted scrapie prions. The tyrosine residue at position 169 is strictly conserved among mammals and an aromatic side chain in this position is essential to maintain a 310-helical turn in the β2-α2 loop. Here we examined the impact of the Y169G substitution together with the previously described S170N, N174T "rigid loop" substitutions on cross-species prion transmission in vivo and in vitro. We found that transgenic mice expressing mouse PrP containing the triple-amino acid substitution completely resisted infection with two strains of mouse prions and with deer chronic wasting disease prions. These studies indicate that Y169 is important for prion formation, and they provide a strong indication that variation of the β2-α2 loop structure can modulate interspecies prion transmission.
authors.affiliation: Departments of Pathology and Medicine, University of California, San Diego, La Jolla, California 92093, CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain, Institut für Molekularbiologie und Biophysik, ETH Zürich, CH-8093 Zürich, Switzerland, Institute of Laboratory Animal Science and Biomodels, University of Veterinary Medicine, 1210 Vienna, Austria, IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain, Department of Integrated Structural and Computational Biology, and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California 92037, UniversitätsSpital Zürich, Institute of Neuropathology, CH-8091 Zürich, Switzerland, and Department of Pathology, Immunology, and Microbiology, University of California, Davis, California 95616.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Kurt
authors.forename: Cyrus
authors.initials: C
authors.lastname: Bett
authors.forename: Natalia
authors.initials: N
authors.lastname: Fernández-Borges
authors.forename: Shivanjali
authors.initials: S
authors.lastname: Joshi-Barr
authors.forename: Simone
authors.initials: S
authors.lastname: Hornemann
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
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
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Sigurdson
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D002417:Cattle; D006224:Cricetinae; D003670:Deer; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017096:Prion Diseases / Q000235:genetics* / Q000517:prevention & control / Q000635:transmission*; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics*; D017433:Protein Structure, Secondary; D012756:Sheep; D013045:Species Specificity
chemical_list: D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse
keywords: TSE; amyloid; conversion; prions; transmission