Immunodetection of disease-associated mutant PrP, which accelerates disease in GSS transgenic mice

The absence of infectivity‐associated, protease‐resistant prion protein (PrPSc) in the brains of spontaneously sick transgenic (Tg) mice overexpressing PrP linked to Gerstmann–Sträussler Scheinker syndrome, and the failure of gene‐targeted mice expressing such PrP to develop disease spontaneously, c...

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Published in:	The EMBO journal Vol. 24; no. 13; pp. 2472 - 2480
Main Authors:	Nazor, Karah E, Kuhn, Franziska, Seward, Tanya, Green, Mike, Zwald, Daniel, Pürro, Mario, Schmid, Jaqueline, Biffiger, Karin, Power, Aisling M, Oesch, Bruno, Raeber, Alex J, Telling, Glenn C
Format:	Journal Article
Language:	English
Published:	Chichester, UK John Wiley & Sons, Ltd 06-07-2005 Blackwell Publishing Ltd
Subjects:	Accumulation Aggregates Animals Antibodies, Monoclonal Brain - metabolism Gerstmann-Straussler-Scheinker Disease - genetics Gerstmann-Straussler-Scheinker Disease - metabolism Gerstmann-Sträussler Scheinker syndrome Immunoblotting Immunoprecipitation Mice Mice, Transgenic Mutants Mutation nucleated polymerization prions Protein Conformation PrPSc Proteins - genetics PrPSc Proteins - immunology PrPSc Proteins - metabolism PrPSc-specific antibody
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Summary:	The absence of infectivity‐associated, protease‐resistant prion protein (PrPSc) in the brains of spontaneously sick transgenic (Tg) mice overexpressing PrP linked to Gerstmann–Sträussler Scheinker syndrome, and the failure of gene‐targeted mice expressing such PrP to develop disease spontaneously, challenged the concept that mutant PrP expression led to spontaneous prion production. Here, we demonstrate that disease in overexpressor Tg mice is associated with accumulation of protease‐sensitive aggregates of mutant PrP that can be immunoprecipitated by the PrPSc‐specific monoclonal antibody designated 15B3. Whereas Tg mice expressing multiple transgenes exhibited accelerated disease when inoculated with disease‐associated mutant PrP, Tg mice expressing mutant PrP at low levels failed to develop disease either spontaneously or following inoculation. These studies indicate that inoculated mutant PrP from diseased mice promotes the aggregation and accumulation of pre‐existing pathological forms of mutant PrP produced as a result of transgene overexpression. Thus, while pathological mutant PrP possesses a subset of PrPSc characteristics, we now show that the attribute of prion transmission suggested by previous studies is more accurately characterized as disease acceleration.
Bibliography:	istex:C00EB8C5EDFD45FA5819825CA6B09C9139621A00 ArticleID:EMBJ7600717 Supplementary Information ark:/67375/WNG-476WS20D-S ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0261-4189 1460-2075
DOI:	10.1038/sj.emboj.7600717