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| Subject Categories: Neuroscience | Molecular Biology of Disease |
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| The EMBO Journal
(2005) 24, 2472–2480, doi:10.1038/sj.emboj.7600717 Published online 16 June 2005 |
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| Immunodetection of disease-associated mutant PrP, which accelerates disease in GSS transgenic mice |
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| Karah E Nazor1, 2, Franziska Kuhn3, Tanya Seward1, Mike Green4, Daniel Zwald3, Mario Pürro3, Jaqueline Schmid3, Karin Biffiger3, Aisling M Power1, Bruno Oesch3, Alex J Raeber3 and Glenn C Telling1, 2, 5, 6 |
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1 Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, USA 2 Graduate Center for Gerontology, University of Kentucky, Lexington, KY, USA 3 Prionics AG, Schlieren, Switzerland 4 UK Transgenic Facility, University of Kentucky, Lexington, KY, USA 5 Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, USA 6 Department of Neurology, University of Kentucky, Lexington, KY, USA To whom correspondence should be addressed Glenn C Telling, Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, 800 Rose Street, Lexington, KY 40536, USA. Tel.: +1 859 323 8564; Fax: +1 859 257 6151; E-mail: gtell2@uky.edu Received 9 March 2005; Accepted 24 May 2005; Published online 16 June 2005. |
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| Abstract |
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| 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. |
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| Keywords: Gerstmann–Sträussler Scheinker syndrome, nucleated polymerization, prions, PrPSc-specific antibody |
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