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Direct Observation of Murine Prion Protein Replication in Vitro.

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cam.issuedOnline2018-10-23
dc.contributor.authorSang, Jason C
dc.contributor.authorMeisl, Georg
dc.contributor.authorThackray, Alana M
dc.contributor.authorHong, Liu
dc.contributor.authorPonjavic, Aleks
dc.contributor.authorKnowles, Tuomas PJ
dc.contributor.authorBujdoso, Raymond
dc.contributor.authorKlenerman, David
dc.contributor.orcidSang, Jason C [0000-0002-8567-5415]
dc.contributor.orcidMeisl, Georg [0000-0002-6562-7715]
dc.contributor.orcidKnowles, Tuomas PJ [0000-0002-7879-0140]
dc.date.accessioned2018-12-07T00:32:02Z
dc.date.available2018-12-07T00:32:02Z
dc.date.issued2018-11-07
dc.description.abstractPrions are believed to propagate when an assembly of prion protein (PrP) enters a cell and replicates to produce two or more fibrils, leading to an exponential increase in PrP aggregate number with time. However, the molecular basis of this process has not yet been established in detail. Here, we use single-aggregate imaging to study fibril fragmentation and elongation of individual murine PrP aggregates from seeded aggregation in vitro. We found that PrP elongation occurs via a structural conversion from a PK-sensitive to PK-resistant conformer. Fibril fragmentation was found to be length-dependent and resulted in the formation of PK-sensitive fragments. Measurement of the rate constants for these processes also allowed us to predict a simple spreading model for aggregate propagation through the brain, assuming that doubling of the aggregate number is rate-limiting. In contrast, while α-synuclein aggregated by the same mechanism, it showed significantly slower elongation and fragmentation rate constants than PrP, leading to much slower replication rate. Overall, our study shows that fibril elongation with fragmentation are key molecular processes in PrP and α-synuclein aggregate replication, an important concept in prion biology, and also establishes a simple framework to start to determine the main factors that control the rate of prion and prion-like spreading in animals.
dc.description.sponsorshipJ. C. S. is supported by a Cambridge Trust Scholarship and a Ministry of Education Technologies Incubation Scholarship, Republic of China (Taiwan). L. H. was supported by the Tsinghua University Initiative Scientific Research Program (Grants 20151080424) and the program of China Scholarships Council (CSC). A. M. T was supported in part by an MRC (NC3Rs) Project (Grant NC/K000462/1). G. M. and T. P. J. K. wish to acknowledge support from Sidney Sussex College Cambridge and the ERC grant PhysProt (337969). A. P. acknowledges funding from EPSRC (Grant EP/L027631/1). D. K. acknowledges funding from the Royal society and an ERC Advanced Grant (669237).
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.33742
dc.identifier.eissn1520-5126
dc.identifier.issn0002-7863
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286433
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Chemical Society (ACS)
dc.publisher.urlhttp://dx.doi.org/10.1021/jacs.8b08311
dc.rightsPublisher's own licence
dc.subjectAnimals
dc.subjectMice
dc.subjectMice, Transgenic
dc.subjectParticle Size
dc.subjectPrions
dc.titleDirect Observation of Murine Prion Protein Replication in Vitro.
dc.typeArticle
dcterms.dateAccepted2018-10-10
prism.endingPage14798
prism.issueIdentifier44
prism.publicationDate2018
prism.publicationNameJ Am Chem Soc
prism.startingPage14789
prism.volume140
pubs.funder-project-idEuropean Research Council (669237)
pubs.funder-project-idNational Centre for the Replacement Refinement and Reduction of Animals in Research (NC/K000462/1)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/J002119/1)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/L027631/1)
pubs.funder-project-idEuropean Research Council (337969)
rioxxterms.licenseref.startdate2018-11
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1021/jacs.8b08311

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