Journal
EMBO JOURNAL
Volume 24, Issue 13, Pages 2472-2480Publisher
WILEY
DOI: 10.1038/sj.emboj.7600717
Keywords
Gerstmann-Straussler Scheinker syndrome; nucleated polymerization; prions; PrPSc-specific antibody
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Funding
- NIAID NIH HHS [N01AI25491] Funding Source: Medline
- NINDS NIH HHS [R01 NS/AI40334] Funding Source: Medline
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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-Straussler 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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