Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection

Haldiman, Tracy; Kim, Chae; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Qing, Liuting; Cohen, Mark L.; Langeveld, J.P.M.; Telling, Glenn C.; Kong, Qingzhong; Safar, Jiri

doi:10.1074/jbc.m113.500108

Cited by 49 publications

(75 citation statements)

References 64 publications

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“…TgNN6h mice express human PrP-129M with the two N-linked glycosylation sites mutated to eliminate glycosylation (24), whereas TgWV mice express wild-type human PrP-129V (25). We observed that TgNN6h and TgWV mice were susceptible to sCJDMM2 or sCJDVV2 prion strains, respectively, after an intracerebral inoculation of 129 polymorphism-matched sCJD brain homogenates; this was confirmed by Western blotting (fig.…”

Section: Resultsmentioning

confidence: 99%

Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease

et al. 2017

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Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is transmissible through iatrogenic routes due to abundant infectious prions [misfolded forms of the prion protein (PrPSc)] in the central nervous system (CNS). Some epidemiological studies have associated sCJD risk with non-CNS surgeries. We explored the potential prion seeding activity and infectivity of skin from sCJD patients. Autopsy or biopsy skin samples from 38 patients [21 sCJD, 2 variant CJD (vCJD), and 15 non-CJD] were analyzed by Western blotting and real-time quaking-induced conversion (RT-QuIC) for PrPSc. Skin samples from two patients were further examined for prion infectivity by bioassay using two lines of humanized transgenic mice. Western blotting revealed dermal PrPSc in one of five deceased sCJD patients and one of two vCJD patients. However, the more sensitive RT-QuIC assay detected prion seeding activity in skin from all 23 CJD decedents but not in skin from any non-CJD control individuals (with other neurological conditions or other diseases) during blinded testing. Although sCJD patient skin contained ~103- to 105-fold lower prion seeding activity than did sCJD patient brain tissue, all 12 mice from two transgenic mouse lines inoculated with sCJD skin homogenates from two sCJD patients succumbed to prion disease within 564 days after inoculation. Our study demonstrates that the skin of sCJD patients contains both prion seeding activity and infectivity, which raises concerns about the potential for iatrogenic sCJD transmission via skin.

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Section: Resultsmentioning

confidence: 99%

Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease

et al. 2017

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“…These findings provided the first experimental evidence for an evolutionary process within the Type 1+2 prion mixture, with selection that favors Type 1 conformers with the lowest stability. 34 The initial preferential amplification rate of Type 1 PrP Sc is not surprising, since there is typically a higher percentage of less stable protease sensitive oligomers in Type 1 PrP Sc , as found in our recent studies. This may explain why this rPrP Sc subtype represents ~70% of all sCJD cases.…”

Section: Mechanism Of Adaptation Evolution and Competition Of Prionsmentioning

confidence: 53%

“…27,32,33 Subsequent experiments with sedimentation velocity separation using high speed centrifugation in sucrose gradient revealed that sCJD prions exist in the continuum of particles composed of <20 to >600 PrP Sc molecules. 34 The fragments were present at different ratios, and indicate co-occurrence of markedly different PrP Sc conformers, often in the same anatomical structure in the same brain. These quantitative findings extended previous qualitative observations with diverse antibodies and western blot techniques.…”

Section: Human Prion Strains and Prion Coexistencementioning

confidence: 99%

“…31,49,51 To investigate the impact of the coexistent prion particle types on this process, we recently used a modified protein misfolding cyclic amplification (PMCA) 52 with homologous, as well as mutant, unglycosylated PrP C(N181, 197Q ) substrate carrying methionine in codon 129. 34 The serial PMCA of "pure" Type MM1 and mixed Type MM1+2 sCJD seeds underwent two distinct phases. In the first adaptation phase, the amplification was limited, and detectable only with CDI.…”

Section: Mechanism Of Adaptation Evolution and Competition Of Prionsmentioning

confidence: 99%

“…[55][56][57][58] Since we observed no direct interaction between different conformers of PrP Sc in our in vitro mixing experiments with "pure" MM1 and MM2 sCJD prions, we concluded that the most likely explanation is competition for PrP C substrate or auxiliary molecule; however, the exact molecular mechanism of this phenomenon remains to be fully elucidated. 34 Cumulatively, the distinct particle size, conformational stability, and amplification rate of these prion subtypes argue for the frequent coexistence of different sCJD prions in the same host (Fig. 1).…”

Section: 54mentioning

confidence: 99%

See 2 more Smart Citations

Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases

Kabir

Safar

2014

Prion

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Ring trial of 2nd generation RT‐QuIC diagnostic tests for sporadic CJD

Orrú

Groveman

Foutz

et al. 2020

Ann Clin Transl Neurol

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Objective: Real-time quaking-induced conversion (RT-QuIC) assays detect prion-seeding activity in a variety of human biospecimens, including cerebrospinal fluid and olfactory mucosa swabs. The assay has shown high diagnostic accuracy in patients with prion disorders. Recently, advances in these tests have led to markedly improved diagnostic sensitivity and reduced assay times. Accordingly, an algorithm has been proposed that entails the use of RT-QuIC analysis of both sample types to diagnose sporadic Creutzfeldt-Jakob disease with nearly 100% accuracy. Here we present a multi-center evaluation (ring trial) of the reproducibility of these improved "second generation" RT-QuIC assays as applied to these diagnostic specimens. Methods: Cerebrospinal fluid samples were analyzed from subjects with sporadic Creutzfeldt-Jakob (n = 55) or other neurological diseases (n = 45) at multiple clinical centers. Olfactory mucosa brushings collected by multiple otolaryngologists were obtained from nine sporadic Creutzfeldt-Jakob disease cases and 19 controls. These sample sets were initially tested blindly by RT-QuIC by a coordinating laboratory, recoded, and then sent to five additional testing laboratories for blinded ring trial testing. Results: Unblinding of the results by a third party indicated 98-100% concordance between the results obtained by the testing of these cerebrospinal fluid and nasal brushings at the six laboratories. Interpretation: This second-generation RT-QuIC assay is highly transferrable, reproducible, and therefore robust for the diagnosis of sporadic Creutzfeldt-Jakob disease in clinical practice.

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Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection

Cited by 49 publications

References 64 publications

Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease

Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease

Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases

Ring trial of 2nd generation RT‐QuIC diagnostic tests for sporadic CJD

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