Dominant-negative inhibition of prion replication in transgenic mice

Perrier, Véronique; Kaneko, Kiyotoshi; Safar, Jiri; Vergara, Julie; Tremblay, Patrick; DeArmond, Stephen J.; Cohen, Fred E.; Prusiner, Stanley B.; Wallace, Andrew

doi:10.1073/pnas.182425299

Cited by 142 publications

(111 citation statements)

References 45 publications

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“…Because we saw no evidence for recruitment of PrP V129 to type 5 PrP Sc in vCJD-inoculated 129MV Tg45͞152 mice, one possibility is that PrP V129 acts to slow the rate of conversion of PrP M129 to type 4 PrP Sc and that this prevents the evolution of florid PrP plaques leading to the uncoupling of vCJD neu- ropathology from propagation of type 4 PrP Sc . This interpretation is consistent with findings from other transgenic studies showing that the kinetics of PrP Sc propagation from one allelic variant of PrP can be dramatically affected by coexpression of nonhomologous PrP (30,32,33).…”

Section: Resultssupporting

confidence: 92%

Dissociation of pathological and molecular phenotype of variant Creutzfeldt–Jakob disease in transgenic human prion protein 129 heterozygous mice

Asante

Linehan²,

Gowland³

et al. 2006

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

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All neuropathologically confirmed cases of variant CreutzfeldtJakob disease (vCJD), characterized by abundant florid plaques and type 4 disease-related prion protein (PrP Sc ) in the brain, have been homozygous for methionine at polymorphic residue 129 of PRNP. The distinctive neuropathological and molecular phenotype of vCJD can be faithfully recapitulated in Prnp-null transgenic mice homozygous for human PrP M129 but not V129, where a distinct prion strain is propagated. Here we model susceptibility of 129MV heterozygotes, the most common PRNP genotype, in transgenic mice and show that, remarkably, propagation of type 4 PrP Sc was not associated with characteristic vCJD neuropathology. Depending on the source of the inoculum these mice can develop four distinct disease phenotypes after challenge with bovine spongiform encephalopathy (BSE) prions or vCJD (human-passaged BSE) prions. vCJD-challenged mice had higher attack rates of prion infection than BSE-challenged recipients. These data argue that human PRNP 129 heterozygotes will be more susceptible to infection with vCJD prions than to cattle BSE prions and may present with a neuropathological phenotype distinct from vCJD.bovine spongiform encephalopathy ͉ prion disease ͉ prion strains ͉ florid plaques ͉ subclinical infection

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Section: Resultssupporting

confidence: 92%

Dissociation of pathological and molecular phenotype of variant Creutzfeldt–Jakob disease in transgenic human prion protein 129 heterozygous mice

Asante

Linehan²,

Gowland³

et al. 2006

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

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“…Nevertheless, other mechanisms for mutation-induced scrapie resistance cannot be ruled out (see below). Similar to observations in sheep, resistance has been observed in transgenic mice in which the Q 3 R mutation had been introduced in mouse PrP at the position corresponding to 171 in sheep (29) and in rabbit cells transfected with OvPrP scrapieresistant variants (30), suggesting that the mechanism for resistance involved, whatever its exact nature, may occur in different mammalian contexts.…”

Section: Structural Correlates Of Sheep Polymorphisms Associated To Ssupporting

confidence: 67%

Insight into the PrP ^C → PrP ^Sc conversion from the structures of antibody-bound ovine prion scrapie-susceptibility variants

Eghiaian

Grosclaude

Lesceu

et al. 2004

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

163

156

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Prion diseases are associated with the conversion of the ␣-helix rich prion protein (PrP C ) into a ␤-structure-rich insoluble conformer (PrP Sc ) that is thought to be infectious. The mechanism for the PrP C 3 PrP Sc conversion and its relationship with the pathological effects of prion diseases are poorly understood, partly because of our limited knowledge of the structure of PrP Sc . In particular, the way in which mutations in the PRNP gene yield variants that confer different susceptibilities to disease needs to be clarified. We report here the 2.5-Å-resolution crystal structures of three scrapie-susceptibility ovine PrP variants complexed with an antibody that binds to PrP C and to PrP Sc ; they identify two important features of the PrP C 3 PrP Sc conversion. First, the epitope of the antibody mainly consists of the last two turns of ovine PrP second ␣-helix. We show that this is a structural invariant in the PrP C 3 PrP Sc conversion; taken together with biochemical data, this leads to a model of the conformational change in which the two PrP C Cterminal ␣-helices are conserved in PrP Sc , whereas secondary structure changes are located in the N-terminal ␣-helix. Second, comparison of the structures of scrapie-sensitivity variants defines local changes in distant parts of the protein that account for the observed differences of PrP C stability, resistant variants being destabilized compared with sensitive ones. Additive contributions of these sensitivity-modulating mutations to resistance suggest a possible causal relationship between scrapie resistance and lowered stability of the PrP protein.

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“…11 [24]. The pH-dependent mobility change in Q168R was also similar to WT* and H186S (data not shown).…”

Section: Influence Of the Pathogenic Mutations On The Conformational mentioning

confidence: 59%

Instability of familial spongiform encephalopathy-related prion mutants

Watanabe

Hiraoka

Shimoyama

et al. 2008

Biochemical and Biophysical Research Communications

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We examined the influence of D177N (D178N in humans) mutation on the conformational stability of the S2 region of moPrP C with varying pHs by using the SDSL-ESR technique. The ESR spectrum of D177N at pH 7.5 was narrower than that of Y161R1, referred to as WT*. The ESR spectrum of D177N did not change when pH in the solution decreased to pH 4.0. Our results suggested that the disappearance of a salt bridge (D177-R163) induced the increase in the instability of S2 region. Moreover, the line shape of the ESR spectrum obtained from H176S neighboring the salt bridge linked to the S2 region was similar to D177N. These results indicate that the protonation of H176 is strongly associated with the stability of S2 region. These findings are important for understanding the mechanism by which the disruption of the salt bridge in the S2 region forms the pathogenic PrP Sc structure in hereditary prion disease.

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Dominant-negative inhibition of prion replication in transgenic mice

Cited by 142 publications

References 45 publications

Dissociation of pathological and molecular phenotype of variant Creutzfeldt–Jakob disease in transgenic human prion protein 129 heterozygous mice

Dissociation of pathological and molecular phenotype of variant Creutzfeldt–Jakob disease in transgenic human prion protein 129 heterozygous mice

Insight into the PrP ^C → PrP ^Sc conversion from the structures of antibody-bound ovine prion scrapie-susceptibility variants

Instability of familial spongiform encephalopathy-related prion mutants

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Dominant-negative inhibition of prion replication in transgenic mice

Cited by 142 publications

References 45 publications

Dissociation of pathological and molecular phenotype of variant Creutzfeldt–Jakob disease in transgenic human prion protein 129 heterozygous mice

Dissociation of pathological and molecular phenotype of variant Creutzfeldt–Jakob disease in transgenic human prion protein 129 heterozygous mice

Insight into the PrP C → PrP Sc conversion from the structures of antibody-bound ovine prion scrapie-susceptibility variants

Instability of familial spongiform encephalopathy-related prion mutants

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Insight into the PrP ^C → PrP ^Sc conversion from the structures of antibody-bound ovine prion scrapie-susceptibility variants