Prions from Sporadic Creutzfeldt-Jakob Disease Patients Propagate as Strain Mixtures

Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently classified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K-digested abnormal prion protein (PrP(res)) isoform identified by Western blotting (type 1 or type 2). Converging evidence led to the view that MM/MV1, VV/MV2, and VV1 and MM2 sCJD cases are caused by distinct prion strains. However, in a significant proportion of sCJD patients, both type 1 and type 2 PrP(res) were reported to accumulate in the brain, which raised questions about the diversity of sCJD prion strains and the coexistence of two prion strains in the same patient. In this study, a panel of sCJD brain isolates (n = 29) that displayed either a single or mixed type 1/type 2 PrP(res) were transmitted into human-PrP-expressing mice (tgHu). These bioassays demonstrated that two distinct prion strains (M1(CJD) and V2(CJD)) were associated with the development of sCJD in MM1/MV1 and VV2/MV2 patients. However, in about 35% of the investigated VV and MV cases, transmission results were consistent with the presence of both M1(CJD) and V2(CJD) strains, including in patients who displayed a “pure” type 1 or type 2 PrP(res). The use of a highly sensitive prion in vitro amplification technique that specifically probes the V2(CJD) strain revealed the presence of the V2(CJD) prion in more than 80% of the investigated isolates, including isolates that propagated as a pure M1(CJD) strain in tgHu. These results demonstrate that at least two sCJD prion strains can be present in a single patient.