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Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson's disease pathogenesis.

cam.issuedOnline2018-09-17
dc.contributor.authorHughes, Craig D
dc.contributor.authorChoi, Minee L
dc.contributor.authorRyten, Mina
dc.contributor.authorHopkins, Lee
dc.contributor.authorDrews, Anna
dc.contributor.authorBotía, Juan A
dc.contributor.authorIljina, Maria
dc.contributor.authorRodrigues, Margarida
dc.contributor.authorGagliano, Sarah A
dc.contributor.authorGandhi, Sonia
dc.contributor.authorBryant, Clare
dc.contributor.authorKlenerman, David
dc.contributor.orcidKlenerman, David [0000-0001-7116-6954]
dc.date.accessioned2018-10-03T04:46:12Z
dc.date.available2018-10-03T04:46:12Z
dc.date.issued2019-01
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 monocytes and that TLR4 expression is highest within human substantia nigra, the most affected brain region, suggesting a role for TLR4 inflammatory responses. We then performed extended incubation of cells with physiological concentrations of small alpha-synuclein oligomers observing the development of a TLR4-dependent sensitized inflammatory 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 alpha-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-Electronic
dc.identifier.doi10.17863/CAM.30481
dc.identifier.eissn1432-0533
dc.identifier.issn0001-6322
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283120
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1007/s00401-018-1907-y
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAggregation
dc.subjectAlpha-synuclein
dc.subjectInnate immunity
dc.subjectParkinson’s disease
dc.subjectTLR4
dc.subjectAnimals
dc.subjectAstrocytes
dc.subjectBrain
dc.subjectCell Death
dc.subjectCytokines
dc.subjectHumans
dc.subjectInflammation
dc.subjectMicroglia
dc.subjectNeurons
dc.subjectParkinson Disease
dc.subjectSubstantia Nigra
dc.subjectToll-Like Receptor 4
dc.subjectalpha-Synuclein
dc.titlePicomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson's disease pathogenesis.
dc.typeArticle
dcterms.dateAccepted2018-09-03
prism.endingPage120
prism.issueIdentifier1
prism.publicationDate2019
prism.publicationNameActa Neuropathol
prism.startingPage103
prism.volume137
pubs.funder-project-idEuropean Research Council (669237)
rioxxterms.licenseref.startdate2019-01
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1007/s00401-018-1907-y

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