Spongiform Encephalopathy in Transgenic Mice Expressing a Point Mutation in the beta 2-alpha 2 Loop of the Prion Protein
2011 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 39, 13840-13847 p.Article in journal (Refereed) Published
Transmissible spongiform encephalopathies are fatal neurodegenerative diseases attributed to misfolding of the cellular prion protein, PrP(C), into a beta-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 beta 2-alpha 2 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 beta 2-alpha 2 loop at 20 degrees 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 beta 2-alpha 2 loop has an important role in intermolecular interactions, including that it may be a key determinant of prion protein aggregation.
Place, publisher, year, edition, pages
Society for Neuroscience , 2011. Vol. 31, no 39, 13840-13847 p.
Engineering and Technology
IdentifiersURN: urn:nbn:se:liu:diva-71550DOI: 10.1523/JNEUROSCI.3504-11.2011ISI: 000295363800016OAI: oai:DiVA.org:liu-71550DiVA: diva2:450528
Funding Agencies|National Institutes of Health| NS055116 NS069566 U54AI065359 |U.S. National Prion Research Program||European Union||Swiss National Science Foundation||Novartis Research Foundation||National Competence Centers for Research on Neural Plasticity and Repair and on Structural Biology||ETH Zurich||European Research Council||2011-10-212011-10-212015-05-28