Abstract
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 (PrPD). 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 PrPD (resPrPD). We recently reported that the sCJDVV1 subtype (129VV homozygosity paired with PrPD type 1, T1) shows an electrophoretic profile where the resPrPD unglycosylated isoform is characterized by either one of two single bands of ~ 20 kDa (T120) and ~ 21 kDa (T121), or a doublet of ~ 21–20 kDa (T121−20). We also showed that T120 and T121 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 T120 and T121 represent distinct prion strains. To answer this question, brain homogenates from sCJDVV cases harboring each of the three resPrPD profiles, were inoculated to transgenic (Tg) mice expressing the human PrP-129M or PrP-129V genotypes. We found that T120 and T121 were faithfully replicated in Tg129V mice. Electrophoretic profile and incubation period of mice challenged with T121−20 resembled those of mice inoculated with T121 and T120, respectively. As in sCJDVV1, Tg129V mice challenged with T121 and T120 generated virtually undistinguishable histotypes. In Tg129M mice, T121 was not replicated while T120 and T121−20 generated a ~ 21–20 kDa doublet after lengthier incubation periods. On second passage, Tg129M mice incubation periods and regional PrP accumulation significantly differed in T120 and T121−20 challenged mice. Combined, these data indicate that T121 and T120 resPrPD represent distinct human prion strains associated with partially overlapping histotypes.
Highlights
For several years sporadic Creutzfeldt–Jakob disease has been grouped into five distinct subtypes, denoted as sCJDMM(MV)1, -MM2, -MV2, -VV1 and -VV2 [18, 38]
Features of PK-resistant PrPD (resPrPD) of the inocula The inocula containing resPrPD T120 were obtained from three cases of sCJDVV1 while inocula harboring T121 and Type 2 (T2) were each isolated from one case of sCJDVV1 and sCJDVV2, respectively; T2 was used as control. T121−20* corresponds to types 1 (T1) variant with a ~ 21–20 kDa doublet co-existing with T2 harvested from a case of sCJDVV1-2 that had histotype mostly consistent with sCJDVV1 (Additional file 5: Table S1)
Ancillary transmission studies with hemizygous Tg129V mice challenged with T120 and T2 isolates led to results similar to those obtained with homozygous mice with the exception of longer incubation periods
Summary
For several years sporadic Creutzfeldt–Jakob disease (sCJD) has been grouped into five distinct subtypes, denoted as sCJDMM(MV)1, -MM2, -MV2, -VV1 and -VV2 [18, 38]. This grouping is based on the combination of two major molecular determinants of the disease phenotype: the methionine (M)/valine (V) polymorphic genotype at codon 129 of the prion protein (PrP), which. SCJDVV1 is distinguishable from the other sCJD subtypes by the type and distribution of the histological lesions (histotype), which include severe spongiform degeneration (SD) with medium size vacuoles throughout the cerebral cortex, presence of ballooned neurons and widespread but light PrP deposition [11]. The histotypes associated with the T120, T121 and T121−20 variants are similar violating the tenet that distinct prion strains are associated with distinct phenotypes [6, 17, 42]
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