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 ß2-α2loop in theNMRstructure 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.