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Updated: Aug 12, 2026
Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
Immunodetection of disease-associated mutant PrP, which accelerates disease in GSS transgenic mice
Karah E Nazor1, Franziska Kuhn, Tanya Seward
1Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
Abstract:
The absence of infectivity-associated, protease-resistant prion protein (PrP(Sc)) 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 PrP(Sc)-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 PrP(Sc) characteristics, we now show that the attribute of prion transmission suggested by previous studies is more accurately characterized as disease acceleration.
Insights
Transgenic mice overexpressing mutant prion protein (PrP) develop disease associated with protease-sensitive PrP aggregates. Inoculated mutant PrP accelerates disease by promoting aggregation of existing pathological PrP, rather than true prion transmission.
Area of Science:
- Neuroscience
- Molecular Biology
- Prion Diseases
Background:
- Gerstmann-Sträussler Scheinker syndrome is linked to mutations in the prion protein (PrP) gene.
- Previous studies suggested mutant PrP expression causes spontaneous prion production and disease.
- The absence of protease-resistant PrP(Sc) in sick transgenic mice challenged this concept.
Purpose of the Study:
- To investigate the nature of prion protein aggregates in transgenic mice overexpressing mutant PrP.
- To determine if mutant PrP expression leads to spontaneous prion production.
- To clarify the mechanism of disease development and transmission in these models.
Main Methods:
- Generation and analysis of transgenic (Tg) mice overexpressing mutant PrP.
- Immunoprecipitation using the PrP(Sc)-specific antibody 15B3.
- Inoculation studies with disease-associated mutant PrP.
Main Results:
- Disease in overexpressor Tg mice correlated with protease-sensitive mutant PrP aggregates.
- These aggregates were immunoprecipitated by the 15B3 antibody.
- Inoculation with mutant PrP accelerated disease in high-expressing Tg mice but not in low-expressing ones.
Conclusions:
- Pathological mutant PrP possesses some PrP(Sc) characteristics but is not infectious in the traditional sense.
- Inoculated mutant PrP promotes aggregation of pre-existing pathological PrP, leading to disease acceleration.
- The phenomenon observed is better described as disease acceleration than prion transmission.
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