title: Spongiform encephalopathy in transgenic mice expressing a point mutation in the β2-α2 loop of the prion protein.
abstract: Transmissible spongiform encephalopathies are fatal neurodegenerative diseases attributed to misfolding of the cellular prion protein, PrP(C), into a β-sheet-rich, aggregated isoform, PrP(Sc). We previously found that expression of mouse PrP with the two amino acid substitutions S170N and N174T, which result in high structural order of the β2-α2 loop in the NMR structure at pH 4.5 and 20°C, caused transmissible de novo prion disease in transgenic mice. Here we report that expression of mouse PrP with the single-residue substitution D167S, which also results in a structurally well ordered β2-α2 loop at 20°C, elicits spontaneous PrP aggregation in vivo. Transgenic mice expressing PrP(D167S) developed a progressive encephalopathy characterized by abundant PrP plaque formation, spongiform change, and gliosis. These results add to the evidence that the β2-α2 loop has an important role in intermolecular interactions, including that it may be a key determinant of prion protein aggregation.
authors.affiliation: Department of Pathology, 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: Shivanjali
authors.initials: S
authors.lastname: Joshi-Barr
authors.forename: Cyrus
authors.initials: C
authors.lastname: Bett
authors.forename: Olivia
authors.initials: O
authors.lastname: Winson
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manco
authors.forename: Petra
authors.initials: P
authors.lastname: Schwarz
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: K Peter R
authors.initials: KP
authors.lastname: Nilsson
authors.forename: Ilan
authors.initials: I
authors.lastname: Margalith
authors.forename: Alex
authors.initials: A
authors.lastname: Raeber
authors.forename: David
authors.initials: D
authors.lastname: Peretz
authors.forename: Simone
authors.initials: S
authors.lastname: Hornemann
authors.forename: Kurt
authors.initials: K
authors.lastname: Wüthrich
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017354:Point Mutation / Q000235:genetics*; D018621:PrPC Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D017096:Prion Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D017433:Protein Structure, Secondary / Q000235:genetics
chemical_list: D018621:PrPC Proteins