Typing prion isoforms

Parchi, Piero; Capellari, Sabina; Chen, Shu G.; Petersen, Robert B.; Kopp, Nicolas; Brown, Paul; Kitamoto, Tetsuyuki; Tateishi, Jun; Giese, Armin; Kretzschmar, Hans A.

doi:10.1038/386232a0

Cited by 251 publications

(213 citation statements)

References 7 publications

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“…It is well known that CJD subtypes significantly differ in the intracerebral distribution of PrP Sc . 21 This is related to the existence of different prion strains and, to a lesser extent, to the host genotype variability such as that determined by the codon 129 polymorphism. Thus, in a CJD case with PrP Sc co-occurrence, it should be expected that the relative amount of the two proteins varies significantly according to the brain area analyzed (Figure 8).…”

Section: Discussionmentioning

confidence: 99%

“…Most significantly, PrP Sc molecules derived from different strains or disease variants with distinct pathology often vary in their N-terminal site of PK cleavage. Based on differences in gel mobility and Nterminal sequence of the core fragments (ie, PrP27-30) generated by PK, Parchi et al 20,21 originally identified two major human PrP Sc types: type 1 with a relative molecular mass of 21 kDa and the primary cleavage site at residue 82 and type 2 with relative molecular mass of 19 kDa and the primary cleavage site at residue 97. 20,21,28 The two PrP Sc types in conjunction with the codon 129 genotype largely explained CJD phenotypic variability and for the first time provided a molecular basis for disease classification (ie, MM1, MM2, VV1, etc).…”

mentioning

confidence: 99%

“…Based on differences in gel mobility and Nterminal sequence of the core fragments (ie, PrP27-30) generated by PK, Parchi et al 20,21 originally identified two major human PrP Sc types: type 1 with a relative molecular mass of 21 kDa and the primary cleavage site at residue 82 and type 2 with relative molecular mass of 19 kDa and the primary cleavage site at residue 97. 20,21,28 The two PrP Sc types in conjunction with the codon 129 genotype largely explained CJD phenotypic variability and for the first time provided a molecular basis for disease classification (ie, MM1, MM2, VV1, etc). 29 More recently, the study of PrP Sc under stringent pH conditions using a gel electrophoresis technique with increased sensitivity demonstrated that PrP Sc types 1 and 2 are heterogeneous species, which can be further distinguished into molecular subtypes that better fit the current histopathological classification of sporadic CJD (sCJD) into six subtypes.…”

mentioning

confidence: 99%

“…Although uncertainties remain on the molecular basis of TSE strains and the relationship between strains and PrP, several lines of evidence indicate that PrP Sc exists in a variety of molecular subtypes showing distinctive physicochemical properties 13,[17][18][19][20][21][22][23][24][25] (for reviews about more recent studies see Parchi et al 26 and Baron et al 27 ). Most significantly, PrP Sc molecules derived from different strains or disease variants with distinct pathology often vary in their N-terminal site of PK cleavage.…”

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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%

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confidence: 99%

mentioning

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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“…Recent studies of PrP Sc from brains of patients who died of vCJD show a pattern of PrP glycoforms different from those found for sCJD or iCJD (315,316). But the utility of measuring PrP glycoforms is questionable in trying to relate BSE to vCJD (317,318) because PrP Sc is formed after the protein is glycosylated (138,140) and enzymatic deglycosylation of PrP Sc requires denaturation (319,320). Alternatively, it may be possible to establish a relationship between the conformations of PrP Sc from cattle with BSE and those from humans with vCJD by using Tg mice as was done for strains generated in the brains of patients with FFI or fCJD (27,180).…”

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Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

Chisholm

Dahlbeck

Krishnamurthy

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

137

138

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Prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). Bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt-Jakob disease (CJD) of humans are among the most notable prion diseases. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrP Sc ). The normal, cellular PrP (PrP C ) is converted into PrP Sc through a posttranslational process during which it acquires a high ␤-sheet content. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrP Sc . Transgenetic studies argue that PrP Sc acts as a template upon which PrP C is refolded into a nascent PrP Sc molecule through a process facilitated by another protein. Miniprions generated in transgenic mice expressing PrP, in which nearly half of the residues were deleted, exhibit unique biological properties and should facilitate structural studies of PrP Sc . While knowledge about prions has profound implications for studies of the structural plasticity of proteins, investigations of prion diseases suggest that new strategies for the prevention and treatment of these disorders may also find application in the more common degenerative diseases.

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Intracerebral distribution of the abnormal isoform of the prion protein in sporadic Creutzfeldt-Jakob disease and fatal insomnia

Parchi

Capellari

2000

Microsc. Res. Tech.

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Typing prion isoforms

Cited by 251 publications

References 7 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

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

Intracerebral distribution of the abnormal isoform of the prion protein in sporadic Creutzfeldt-Jakob disease and fatal insomnia

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