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dc.contributor.authorFuster-Matanzo, Almudenaen
dc.contributor.authorJurado-Arjona, Jerónimoen
dc.contributor.authorBenvegnù, Stefanoen
dc.contributor.authorGarcía, Estheren
dc.contributor.authorMartín-Maestro, Patriciaen
dc.contributor.authorGómez-Sintes, Raquelen
dc.contributor.authorHernández, Félixen
dc.contributor.authorÁvila, Jesúsen
dc.date.accessioned2017-01-27T14:27:15Z
dc.date.available2017-01-27T14:27:15Z
dc.date.issued2017-03en
dc.identifier.issn1420-682X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/262089
dc.description.abstractGlycogen synthase kinase-3β (GSK-3β) is a serine-threonine kinase implicated in multiple processes and signaling pathways. Its dysregulation is associated with different pathological conditions including Alzheimer's disease (AD). Here we demonstrate how changes in GSK-3β activity and/or levels regulate the production and subsequent secretion of fractalkine, a chemokine involved in the immune response that has been linked to AD and to other different neurological disorders. Treatment of primary cultured neurons with GSK-3β inhibitors such as lithium and AR-A014418 decreased full-length fractalkine in total cell extracts. Opposite effects were observed after neuron transduction with a lentiviral vector overexpressing the kinase. Biotinylation assays showed that those changes mainly affect the plasma membrane-associated form of the protein, an observation that positively correlates with changes in the levels of its soluble form. These effects were confirmed in lithium-treated wild type (wt) mice and in GSK-3β transgenic animals, as well as in brain samples from AD patients, evident as age-dependent (animals) or Braak stage dependent changes (humans) in both the membrane-bound and the soluble forms of the protein. Further immunohistochemical analyses demonstrated how GSK-3β exerts these effects by affecting the trafficking of the chemokine from the Golgi to the plasma membrane, in different and opposite ways when the levels/activity of the kinase are increased or decreased. This work provides for the first time a mechanism linking GSK-3β and fractalkine both in vitro and in vivo, with important implications for neurological disorders and especially for AD, in which levels of this chemokine might be useful as a diagnostic tool.
dc.description.sponsorshipThis study was funded by grants from Spanish Ministry of Economy and Competitiveness (SAF 2006-02424, BFU-2008-03980, BFU-2010-21507), Comunidad de Madrid (SAL/0202/2006), Fundación M. Botín, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), and an institutional grant from the Fundación R. Areces. Authors would like to thank Dr. Alberto Rábano (Neuropathology Department, CIEN Foundation, Madrid, Spain) for the human brain samples, people from Laboratory 122 from the Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain, for the constant help and technical support and Dr. Jayden A. Smith (Clinical Neurosciences Deparment, University of Cambridge) for kindly revising and correcting English grammar.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.language.isoenen
dc.publisherSpringer
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectCell Membraneen
dc.subjectTransport Vesiclesen
dc.subjectGolgi Apparatusen
dc.subjectAnimalsen
dc.subjectMice, Inbred C57BLen
dc.subjectHumansen
dc.subjectAlzheimer Diseaseen
dc.subjectrab GTP-Binding Proteinsen
dc.subjectProtein Bindingen
dc.subjectProtein Transporten
dc.subjectSolubilityen
dc.subjectChemokine CX3CL1en
dc.subjectGlycogen Synthase Kinase 3 betaen
dc.titleGlycogen synthase kinase-3β regulates fractalkine production by altering its trafficking from Golgi to plasma membrane: implications for Alzheimer's disease.en
dc.typeArticle
prism.endingPage1163
prism.publicationDate2017en
prism.publicationNameCellular and molecular life sciences : CMLSen
prism.startingPage1153
prism.volume74en
dc.identifier.doi10.17863/CAM.7337
dcterms.dateAccepted2016-11-02en
rioxxterms.versionofrecord10.1007/s00018-016-2408-6en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-03en
dc.identifier.eissn1420-9071
rioxxterms.typeJournal Article/Reviewen
cam.orpheus.successThu Jan 30 12:56:36 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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