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


Sigurdson, C J; Joshi-Barr, S; Bett, C; Winson, O; Manco, G; Schwarz, P; Rülicke, T; Nilsson, K P R; Margalith, I; Raeber, A; Peretz, D; Hornemann, S; Wüthrich, K; Aguzzi, A (2011). Spongiform encephalopathy in transgenic mice expressing a point mutation in the β2-α2 loop of the prion protein. Journal of Neuroscience, 31(39):13840-13847.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2011
Deposited On:10 Nov 2011 13:18
Last Modified:05 Apr 2016 15:05
Publisher:Society for Neuroscience
ISSN:0270-6474
Publisher DOI:10.1523/JNEUROSCI.3504-11.2011
PubMed ID:21957246
Permanent URL: http://doi.org/10.5167/uzh-50718

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