Beyond PrPres Type 1/Type 2 Dichotomy in Creutzfeldt-Jakob Disease

Abstract

Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K (PK) digested abnormal prion protein (PrPres) identified on Western blotting (type 1 or type 2). These biochemically distinct PrPres types have been considered to represent potential distinct prion strains. However, since cases of CJD show co-occurrence of type 1 and type 2 PrPres in the brain, the basis of this classification system and its relationship to agent strain are under discussion. Different brain areas from 41 sCJD and 12 iatrogenic CJD (iCJD) cases were investigated, using Western blotting for PrPres and two other biochemical assays reflecting the behaviour of the disease-associated form of the prion protein (PrPSc) under variable PK digestion conditions. In 30% of cases, both type 1 and type 2 PrPres were identified. Despite this, the other two biochemical assays found that PrPSc from an individual patient demonstrated uniform biochemical properties. Moreover, in sCJD, four distinct biochemical PrPSc subgroups were identified that correlated with the current sCJD clinico-pathological classification. In iCJD, four similar biochemical clusters were observed, but these did not correlate to any particular PRNP 129 polymorphism or western blot PrPres pattern. The identification of four different PrPSc biochemical subgroups in sCJD and iCJD, irrespective of the PRNP polymorphism at codon 129 and the PrPres isoform provides an alternative biochemical definition of PrPSc diversity and new insight in the perception of Human TSE agents variability.

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

“…VV2A) has similar results than dividing the patients in relation only to PRNP codon 129 polymorphism. Therefore, it seems that PRNP polymorphism has a stronger influence than PrP-type on markers sensitivity, which is in agreement with the co-occurrence of type 1 and type 2 PrP in the brain of sCJD patients [35]. This seems to argue against the conventional classification of molecular subtypes into classical and non-classical, and might be of relevance to patients diagnosis, since PRNP polymorphism is the only characteristic that can be determined during the patient life.…”

“…Significantly lower p-tau181 levels were associated with the classical molecular subtype (classical = 32.9 ± 5.6 pg/mL; non-classical = 60.6 ± 10.4 pg/mL; P \ 0.05). Since cases of sCJD show co-occurrence of type 1 and type 2 PrP in the brain [35], and knowing that codon 129 genotype influences the course of the disease, we have re-analysed the influence of molecular subtype considering three different subtypes: MM1; MV1 ? MV2A and VV1 ?…”

Involvement of Dab1 in APP processing and β-amyloid deposition in sporadic Creutzfeldt–Jakob patients

“…PrP sc inoculation gives rise to a wide range of molecular responses in infected brains (Xiang et al, 2004) including in oxidative stress (Choi et al, 1998;Martin et al, 2007;Yun et al, 2006), which is also described in sCJD patients (Freixes et al, 2006;Pamplona et al, 2008;Petersen et al, 2005). Indeed, sCJD patients with PrP sc type 1 and MM polymorphism at codon 129 are characterized by faster evolution and decreased life expectancy compared with PrP sc type 2 with other polymorphisms at codon 129 (Uro-Coste et al, 2008). These data suggest that oxidative abnormalities in sCJD patients with PrP sc type 1 may alter Dab1 function, impairing normal APP processing and decreasing A production.…”

Cerebrospinal fluid tau levels are a marker for molecular subtype in sporadic Creutzfeldt-Jakob disease

“…Moreover, we did not find systematic differences in age, sex or duration of disease between sCJD patients with a definite molecular subtype and those without (probable and possible sCJD cases according to the updated CJD criteria ), when reviewing all patients referred to the German National Reference Center between 2001 and 2012. Another limitation of our study is, that we were not able to take into account sCJD patients with mixed PrP type 1/2 subtypes which have been described in recent years (Puoti, et al, 1999,Uro-Coste, et al, 2008 as there were only few cases available in our surveillance study. The presence of mixed subtypes adds more complexity to subtype differentiation and might decrease the diagnostic validity of tau as a subtype-specific marker.…”