Sporadic Creutzfeldt-Jakob disease: Co-occurrence of different types of PrP
            <sup>Sc</sup>
            in the same brain

Puoti, Gianfranco; Giaccone, Giorgio; Rossi, Giacomina; Canciani, Barbara; Bugiani, Orso; Tagliavini, Fabrizio

doi:10.1212/wnl.53.9.2173

Cited by 171 publications

(130 citation statements)

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“…Difficulties in current CJD postmortem diagnostics relate to the finding of PrP Sc types coexistence in the brains. CJD cases with mixed molecular and pathological features have been reported in several studies, 29,[31][32][33] but no criteria have been established for the correct biochemical biologically relevant identification of PrP Sc types co-occurrences. Furthermore, it is still unclear to what extent current molecular techniques allow the detection of the whole spectrum of such cases.…”

Section: Discussionmentioning

confidence: 99%

“…29,31 To see whether similar regional variations are observed in the type 1-like and type 2 ratio, we analyzed different areas of type 2 sCJD cases after PK digestion in standardized and homogenous conditions. In particular, much attention was given to performing PK digestion of tissue homogenate at a given pH value (using a high buffer capacity solution) and at a given total protein concentration.…”

Section: Regional Variations Of Prp Sc Type 1 and 2 Co-occurrencementioning

confidence: 99%

“…Originally reported by Parchi et al, 29 the existence of CJD subjects with mixed molecular and pathological phenotypes has been confirmed in subsequent studies. [31][32][33] Nevertheless, difficulties remain in understanding both the biological basis of this phenomenon and its prevalence. The issue has become particularly puzzling after two recent studies 34,35 took advantage of monoclonal antibodies recognizing an epitope between residues 82 and 96 of human PrP located outside the primary PK cleavage site of type 2 PrP Sc .…”

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confidence: 99%

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A refined method for molecular typing reveals that co-occurrence of PrPSc types in Creutzfeldt–Jakob disease is not the rule

Notari

Capellari

Langeveld

et al. 2007

Laboratory Investigation

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Molecular typing in Creutzfeldt-Jakob disease (CJD) relies on the detection of distinct protease-resistant prion protein (PrP Sc ) core fragments, which differ in molecular mass or glycoform ratio. However, the definition and correct identification of CJD cases with a co-occurrence of PrP Sc types remains a challenge. With antibodies recognizing a linear epitope in the octapeptide repeat PrP region, supposed to distinguish between the two major PrP Sc isoforms (ie, types 1 and 2), it was recently shown that all type 2 cases display an associated band with a type 1 migration pattern, which led to the conclusion that multiple PrP Sc types regularly coexist in CJD. We studied brain samples from 53 sporadic CJD and 4 variant CJD subjects using a high-resolution electrophoresis, a wide range of proteinase K (PK) activities, the 'type 1-selective' antibody 12B2, and several unselective antibodies. We found that the type 1-like band detected by 12B2 in all CJD subtypes associated with PrP Sc type 2 is not a PK-resistant PrP Sc core but rather matches the physicochemical properties of partially cleaved fragments, which result from the several PK cleavage sites included in the N-terminal portion of PrP Sc . Furthermore, using gels with high resolution and a relatively high PK activity, we were able to increase the detection sensitivity of either type 1 or 2, when coexisting, to amount corresponding to 3-5% of the total PrP Sc signal (ie, weak band of one type/total PrP Sc ). Our results show that there are many pitfalls associated with the use of 'type 1 selective' antibodies for CJD typing studies and that co-occurrence of PrP Sc types in CJD is not the rule. The present results further validate the rationale basis of current CJD classification and the qualitative nature of molecular typing in CJD.

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Section: Discussionmentioning

confidence: 99%

Section: Regional Variations Of Prp Sc Type 1 and 2 Co-occurrencementioning

confidence: 99%

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confidence: 99%

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A refined method for molecular typing reveals that co-occurrence of PrPSc types in Creutzfeldt–Jakob disease is not the rule

Notari

Capellari

Langeveld

et al. 2007

Laboratory Investigation

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“…4 Recent reports show that certain cases of sCJD contain both type 1 and 2 in the same brain. [5][6][7][8] Regional variation in PrP Sc type has subsequently been reported in iatrogenic CJD 9 and in familial CJD, 10 suggesting that co-occurrence of different PrP Sc types is perhaps the rule in CJD. In contrast, all of the available evidence so far has suggested that the variant CJD (vCJD) brain contains a single type, which has been interpreted to reflect infection of susceptible individuals by a single defined pathogen, namely bovine spongiform encephalopathy (BSE).…”

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confidence: 99%

Detection of Type 1 Prion Protein in Variant Creutzfeldt-Jakob Disease

Yull

Ritchie

Langeveld³

et al. 2006

The American Journal of Pathology

113

107

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Molecular typing of the abnormal form of the prion protein (PrP Sc) has come to be regarded as a powerful tool in the investigation of the prion diseases. All evidence thus far presented indicates a single PrP Sc molecular type in variant Creutzfeldt-Jakob disease (termed type 2B), presumably resulting from infection with a single strain of the agent (bovine spongiform encephalopathy). Here we show for the first time that the PrP Sc that accumulates in the brain in variant CreutzfeldtJakob disease also contains a minority type 1 component. This minority type 1 PrP Sc was found in all 21 cases of variant Creutzfeldt-Jakob disease tested, irrespective of brain region examined, and was also present in the variant Creutzfeldt-Jakob disease tonsil. The quantitative balance between PrPSc types was maintained when variant Creutzfeldt-Jakob disease was transmitted to wild-type mice and was also found in bovine spongiform encephalopathy cattle brain, indicating that the agent rather than the host specifies their relative representation. These results indicate that PrP Sc molecular typing is based on quantitative rather than qualitative phenomena and point to a complex relationship between prion protein biochemistry, disease phenotype and agent strain.

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“…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.…”

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confidence: 99%

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

Karch¹,

Hermann²,

Ponto³

et al. 2015

Neurobiology of Aging

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CitationCerebrospinal fluid tau levels are a marker for molecular subtype in sporadic Creutzfeldt-Jakob disease. 2015, 36 Abstract:The molecular subtype of sporadic Creutzfeldt-Jakob disease (sCJD) is an important prognostic marker for patient survival. However, subtype determination is not possible during life-time. Since the rate of disease progression is associated with the molecular subtype, this study aimed at investigating if total tau, a marker of neuronal death, allows pre-mortem diagnosis of molecular subtype when codon 129 genotype is known.296 sCJD patients were tested for their cerebrospinal fluid total tau level at time of diagnosis and were investigated for their sCJD subtype post-mortem.There was a significant association between tau levels and the prion protein type in patients with Highlights: To date, subtype determination in Creutzfeldt-Jakob disease is only possible post-mortem  We investigate if total tau can be used as a subtype-specific marker for Creutzfeldt-Jakob disease  In our study we show that total tau has a good diagnostic validity when codon 129 genotype is known  Thus, we propose the combination of total tau and codon 129 genotype as a new test for molecular subtype  This approach provides valuable information for caretakers about the further course of disease

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Sporadic Creutzfeldt-Jakob disease: Co-occurrence of different types of PrP ^Sc in the same brain

Cited by 171 publications

References 11 publications

A refined method for molecular typing reveals that co-occurrence of PrPSc types in Creutzfeldt–Jakob disease is not the rule

A refined method for molecular typing reveals that co-occurrence of PrPSc types in Creutzfeldt–Jakob disease is not the rule

Detection of Type 1 Prion Protein in Variant Creutzfeldt-Jakob Disease

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

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Sporadic Creutzfeldt-Jakob disease: Co-occurrence of different types of PrP Sc in the same brain

Cited by 171 publications

References 11 publications

A refined method for molecular typing reveals that co-occurrence of PrPSc types in Creutzfeldt–Jakob disease is not the rule

A refined method for molecular typing reveals that co-occurrence of PrPSc types in Creutzfeldt–Jakob disease is not the rule

Detection of Type 1 Prion Protein in Variant Creutzfeldt-Jakob Disease

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

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Sporadic Creutzfeldt-Jakob disease: Co-occurrence of different types of PrP ^Sc in the same brain