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dc.contributor.authorHughes, Craigen
dc.contributor.authorChoi, Minee Len
dc.contributor.authorRyten, Minaen
dc.contributor.authorHopkins, Leeen
dc.contributor.authorDrews, Annaen
dc.contributor.authorBotía, Juan Aen
dc.contributor.authorIljina, Mariaen
dc.contributor.authorRodrigues, Margaridaen
dc.contributor.authorGagliano, Sarah Aen
dc.contributor.authorGandhi, Soniaen
dc.contributor.authorBryant, Clareen
dc.contributor.authorKlenerman, Daviden
dc.date.accessioned2018-10-03T04:46:12Z
dc.date.available2018-10-03T04:46:12Z
dc.date.issued2019-01en
dc.identifier.issn0001-6322
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283120
dc.description.abstractDespite the wealth of genomic and transcriptomic data in Parkinson’s disease (PD), the initial molecular events are unknown. Using LD score regression analysis we show significant enrichment in PD heritability within regulatory sites for LPS-activated mono-cytes and that TLR4 expression is highest within human substantia nigra, the most af-fected brain region, suggesting a role for TLR4 inflammatory responses. We then per-formed extended incubation of cells with physiological concentrations of small alpha synuclein oligomers observing the development of a TLR4-dependent sensitized in-flammatory response with time, including TNF-α production. ROS and cell death in primary neuronal cultures were significantly reduced by TLR4 antagonists revealing that an indirect inflammatory mechanism involving cytokines produced by glial cells makes a major contribution to neuronal death. Prolonged exposure to low levels of al-pha synuclein oligomers sensitizes TLR4 responsiveness in astrocytes and microglial, explaining how they become pro-inflammatory, and may be an early causative event in PD.
dc.description.sponsorshipThis work was supported by ARUK. AD was financed by a Herchel Smith Postdoctor-al Fellowship. DK acknowledges funding from the Royal Society and ERC Advanced Grant (669237). SG and ML acknowledge funding by Wellcome.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherSpringer Nature
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectBrainen
dc.subjectSubstantia Nigraen
dc.subjectAstrocytesen
dc.subjectMicrogliaen
dc.subjectNeuronsen
dc.subjectAnimalsen
dc.subjectHumansen
dc.subjectParkinson Diseaseen
dc.subjectInflammationen
dc.subjectCytokinesen
dc.subjectCell Deathen
dc.subjectToll-Like Receptor 4en
dc.subjectalpha-Synucleinen
dc.titlePicomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson's disease pathogenesis.en
dc.typeArticle
prism.endingPage120
prism.issueIdentifier1en
prism.publicationDate2019en
prism.publicationNameActa neuropathologicaen
prism.startingPage103
prism.volume137en
dc.identifier.doi10.17863/CAM.30481
dcterms.dateAccepted2018-09-03en
rioxxterms.versionofrecord10.1007/s00401-018-1907-yen
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-01en
dc.contributor.orcidRodrigues, Margarida [0000-0001-6364-7125]
dc.contributor.orcidBryant, Clare [0000-0002-2924-0038]
dc.contributor.orcidKlenerman, David [0000-0001-7116-6954]
dc.identifier.eissn1432-0533
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (669237)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International