Recombinant Human Prion Protein Inhibits Prion Propagation in vitro

Yuan, Jing; Zhan, Yi; Abskharon, Romany; Xiao, Xinxin; Martinez, Manuel Camacho; Zhou, Xiaochen; Kneale, Geoff; Mikol, Jacqueline; Lehmann, Sylvain; Surewicz, Witold K.; Castilla, Joaquı́n; Steyaert, Jan; Zhang, Shulin Na; Kong, Qingzhong; Petersen, Robert B.; Wohlkonig, A.; Zou, Wen-Quan

doi:10.1038/srep02911

Cited by 29 publications

(63 citation statements)

References 54 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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“…In fact, some studies support the view that anchorless versions of PrP C either directly inhibit the conversion to PrP Sc or at least are less efficiently converted compared to membrane-anchored forms. 43,[68][69][70][71] Fitting to this model, impaired production of shed PrP C in our ADAM10 cKO mice (possibly in connection with increased PrP C surface levels) resulted in increased PrP Sc formation 39 , whereas overexpression of ADAM10 leads to decreased production of PrP Sc . 34 Further support for this model might come from bank voles: this animal model has raised attention in prion research due to its high susceptibility to different sources of prions.…”

Section: Inhibition Of Prp Sc Formation By Shed Prp?mentioning

confidence: 74%

Shedding light on prion disease

Glatzel

Linsenmeier

Dohler³

et al. 2015

Prion

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Proteolytic processing regulates key processes in health and disease. The cellular prion protein (PrP(C)) is subject to at least 3 cleavage events, α-cleavage, β-cleavage and shedding. In contrast to α- and β-cleavage where there is an ongoing controversy on the identity of relevant proteases, the metalloprotease ADAM10 represents the only relevant PrP sheddase. Here we focus on the roles that ADAM10-mediated shedding of PrP(C) and its pathogenic isoform (PrP(Sc)) might play in regulating their physiological and pathogenic functions, respectively. As revealed by our recent study using conditional ADAM10 knockout mice (Altmeppen et al., 2015), shedding of PrP seems to be involved in key processes of prion diseases. These aspects and several open questions arising from them are discussed. Increased knowledge on this topic can shed new light on prion diseases and other neurodegenerative conditions as well.

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“…In agreement with this result, recombinant PrP reduces prion conversion in vitro by binding to PrP res and preventing PrP res /PrP C interactions. 6 Third, PrPC1 produced after PrP C α-cleavage is not a substrate for prion conversion. In contrast, PrPC1 acts as a dominant-negative inhibitor of PrP res mediated-conversion suggesting that an incomplete PrP C molecule at the cell surface can trap PrP res into a non-convertible complex.…”

Section: Secreted Forms Of Prp C In Prion Diseasesmentioning

confidence: 99%

“…PrP C is composed of an unstructured N-terminal domain and a structured C-terminal domain with three α-helices and two short β-sheets. 5 Both domain are essential for efficient conversion of PrP C into PrP res 6,7 . PrP C has a dual function in prion diseases.…”

Section: Secreted Forms Of Prp C In Prion Diseasesmentioning

confidence: 99%