Spongiform encephalopathy in transgenic mice expressing a point mutation in the β2-α2 loop of the prion protein

• Published in: The Journal of neuroscience 2011-09, Vol.31 (39), p.13840-13847
• Main Authors: Sigurdson, Christina J, Joshi-Barr, Shivanjali, Bett, Cyrus, Winson, Olivia, Manco, Giuseppe, Schwarz, Petra, Rülicke, Thomas, Nilsson, K Peter R, Margalith, Ilan, Raeber, Alex, Peretz, David, Hornemann, Simone, Wüthrich, Kurt, Aguzzi, Adriano
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution - genetics; Animals; Female; Male; Mice; Mice, Knockout; Mice, Transgenic; Point Mutation - genetics; Prion Diseases - diagnosis; Prion Diseases - genetics; Prion Diseases - metabolism; Protein Structure, Secondary - genetics; PrPC Proteins - biosynthesis; PrPC Proteins - genetics; PrPC Proteins - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3504-11.2011

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.