Two distinct conformers of PrP(D) type 1 of sporadic Creutzfeldt–Jakob disease with codon 129VV genotype faithfully propagate in vivo

Current classifications of sporadic Creutzfeldt–Jakob disease (sCJD) identify five subtypes associated with different disease phenotypes. Most of these histopathological phenotypes (histotypes) co-distribute with distinct pairings of methionine (M)/valine (V) genotypes at codon 129 of the prion protein (PrP) gene and the type (1 or 2) of the disease-associated PrP (PrP(D)). Types 1 and 2 are defined by the molecular mass (~ 21 kDa and ~ 19 kDa, respectively) of the unglycosylated isoform of the proteinase K-resistant PrP(D) (resPrP(D)). We recently reported that the sCJDVV1 subtype (129VV homozygosity paired with PrP(D) type 1, T1) shows an electrophoretic profile where the resPrP(D) unglycosylated isoform is characterized by either one of two single bands of ~ 20 kDa (T1(20)) and ~ 21 kDa (T1(21)), or a doublet of ~ 21–20 kDa (T1(21−20)). We also showed that T1(20) and T1(21) in sCJDVV have different conformational features but are associated with indistinguishable histotypes. The presence of three distinct molecular profiles of T1 is unique and raises the issue as to whether T1(20) and T1(21) represent distinct prion strains. To answer this question, brain homogenates from sCJDVV cases harboring each of the three resPrP(D) profiles, were inoculated to transgenic (Tg) mice expressing the human PrP-129M or PrP-129V genotypes. We found that T1(20) and T1(21) were faithfully replicated in Tg129V mice. Electrophoretic profile and incubation period of mice challenged with T1(21−20) resembled those of mice inoculated with T1(21) and T1(20), respectively. As in sCJDVV1, Tg129V mice challenged with T1(21) and T1(20) generated virtually undistinguishable histotypes. In Tg129M mice, T1(21) was not replicated while T1(20) and T1(21−20) generated a ~ 21–20 kDa doublet after lengthier incubation periods. On second passage, Tg129M mice incubation periods and regional PrP accumulation significantly differed in T1(20) and T1(21−20) challenged mice. Combined, these data indicate that T1(21) and T1(20) resPrP(D) represent distinct human prion strains associated with partially overlapping histotypes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01132-7.