RT Journal Article
SR Electronic
T1 Spongiform Encephalopathy in Transgenic Mice Expressing a Point Mutation in the β2–α2 Loop of the Prion Protein
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 13840
OP 13847
DO 10.1523/JNEUROSCI.3504-11.2011
VO 31
IS 39
A1 Sigurdson, Christina J.
A1 Joshi-Barr, Shivanjali
A1 Bett, Cyrus
A1 Winson, Olivia
A1 Manco, Giuseppe
A1 Schwarz, Petra
A1 Rülicke, Thomas
A1 Nilsson, K. Peter R.
A1 Margalith, Ilan
A1 Raeber, Alex
A1 Peretz, David
A1 Hornemann, Simone
A1 Wüthrich, Kurt
A1 Aguzzi, Adriano
YR 2011
UL http://www.jneurosci.org/content/31/39/13840.abstract
AB Transmissible spongiform encephalopathies are fatal neurodegenerative diseases attributed to misfolding of the cellular prion protein, PrPC, into a β-sheet-rich, aggregated isoform, PrPSc. 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 PrPD167S 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.