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dc.contributor.authorStott, Simonen
dc.contributor.authorRandle, Suzanneen
dc.contributor.authorAl Rawi, Saraen
dc.contributor.authorRowicka, Paulinaen
dc.contributor.authorHarris, Rebeccaen
dc.contributor.authorMason, Bethanyen
dc.contributor.authorXia, Jingen
dc.contributor.authorDalley, Jeffreyen
dc.contributor.authorBarker, Rogeren
dc.contributor.authorLaman, Heikeen
dc.date.accessioned2019-05-10T23:30:56Z
dc.date.available2019-05-10T23:30:56Z
dc.date.issued2019-08-06en
dc.identifier.issn1096-9896
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/292689
dc.description.abstractThe field of Parkinson’s disease research has been impeded by the absence of animal models that clearly phenocopy the features of this neurodegenerative condition. Mutations in FBXO7/PARK15 are associated with both sporadic Parkinson’s disease and a severe form of autosomal recessive early-onset Parkinsonism. Here we report that conditional deletion of Fbxo7 in the midbrain dopamine neurons results in an early reduction in striatal dopamine levels, together with a slow, progressive loss of midbrain dopamine neurons and onset of locomotor defects. Unexpectedly, a later compensatory response led to a near-full restoration of dopaminergic fibre innervation in the striatum, but nigral cell loss was irreversible. Mechanistically, there was increased expression in the dopamine neurons of FBXO7-interacting protein, RPL23, which is a sensor of ribosomal stress that inhibits MDM2, the negative regulator of p53. A corresponding activated p53 transcriptional signature biased towards pro-apoptotic genes was also observed. These data suggest the neuroprotective role of FBXO7 involves its suppression of the RPL23-MDM2-p53 axis that promotes cell death in dopaminergic midbrain neurons.
dc.description.sponsorshipBiotechnology and Biological Sciences Research Council (BB/J007846/1), DDPDgenes, Parkinson's UK and the CurePD Trust, and Wellcome Trust-MRC funded Cambridge Stem Cell Institute and an NIHR award of a Biomedical Research Centre for Addenbrooke’s Hospital/University of Cambridge.
dc.publisherJohn Wiley & Sons Inc.
dc.rightsAll rights reserved
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleLoss of FBXO7 results in a Parkinson’s-like dopaminergic degeneration via an RPL23-MDM2-TP53 pathwayen
dc.typeArticle
prism.endingPage254
prism.issueIdentifier2en
prism.publicationDate2019en
prism.publicationNameJournal of Pathologyen
prism.startingPage241
prism.volume249en
dc.identifier.doi10.17863/CAM.39842
dcterms.dateAccepted2019-05-09en
rioxxterms.versionofrecord10.1002/path.5312en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2019-08-06en
dc.contributor.orcidHarris, Rebecca [0000-0002-5854-4700]
dc.contributor.orcidMason, Bethany [0000-0002-1157-0469]
dc.contributor.orcidDalley, Jeffrey [0000-0002-2282-3660]
dc.contributor.orcidBarker, Roger [0000-0001-8843-7730]
dc.contributor.orcidLaman, Heike [0000-0002-6089-171X]
dc.identifier.eissn1096-9896
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idBBSRC (BB/J007846/1)
pubs.funder-project-idRoyal Society (RG2010/R2)
pubs.funder-project-idRosetrees Trust (A784)
pubs.funder-project-idParkinson's UK (G-1701)
pubs.funder-project-idMRC (MC_PC_12009)
cam.issuedOnline2019-05-29en


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