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dc.contributor.authorUlbrich, Lisaen
dc.contributor.authorFavaloro, Flores Liettaen
dc.contributor.authorTrobiani, Lauraen
dc.contributor.authorMarchetti, Valentinaen
dc.contributor.authorPatel, Vrutien
dc.contributor.authorPascucci, Tizianaen
dc.contributor.authorComoletti, Davideen
dc.contributor.authorMarciniak, Stefanen
dc.contributor.authorde, Jaco Antonellaen
dc.date.accessioned2016-01-08T16:44:20Z
dc.date.available2016-01-08T16:44:20Z
dc.date.issued2015-11-30en
dc.identifier.citationBiochemical Journal 2015. doi:10.1042/BJ20150274en
dc.identifier.issn0264-6021
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/253181
dc.description.abstractSeveral forms of monogenic heritable autism spectrum disorders are associated to mutations in the neuroligin genes. The autism-linked substitution arginine 451 to cysteine (R451C) in neuroligin3induces local misfolding of its extracellular domain, causing partial retention in the endoplasmic reticulum (ER) of expressing cells. We have generated a PC12 Tet-On cell model system with inducible expression of wild type or R451C neuroligin3 to investigate if there is activation of the unfolded protein response (UPR) as a result of misfolded protein retention. As a positive control for protein misfolding, we also expressed the severely disrupted mutant G221R neuroligin3, which is known to be completely retained within the ER. Our data show that overexpression of either R451C or G221R mutant proteins leads to the activation of all three signaling branches of the UPR downstream of the stress sensors ATF6, IRE1 and PERK. Each branch displayed different activation profiles that partially correlated with the degree of misfolding caused by each mutation. We also show that upregulation of BiP and CHOP was induced by both mutant proteins but not by wild type neuroligin3, both in proliferative cells and cells differentiated to a neuronal–like phenotype. Collectively, our data show that mutant R451C neuroligin3 activates the UPR in a novel cell model system, suggesting that this cellular response may have a role in monogenic forms of autism characterized by misfolding mutations.
dc.description.sponsorshipThis work was supported by: Compagnia San Paolo, Sapienza University of Rome and Pasteur Institute - Cenci Bolognetti Foundation grants to ADJ. SJM is a MRC Senior Clinical Research Fellow [MRC Ref G1002610]. This work was also supported by National Institutes of Health grants (MH092906), from the Robert Wood Johnson Foundation to the Child Health Institute of New Jersey [grant #67038] and to the Governor's Council for Medical Research and Treatment of Autism [CAUT14APL028] to D.C.
dc.languageEnglishen
dc.language.isoenen
dc.publisherPortland Press
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectneuroliginen
dc.subjectER stressen
dc.subjectunfolded protein responseen
dc.subjectautismen
dc.subjectprotein misfoldingen
dc.subjectmolecular chaperonesen
dc.titleAutism associated R451C mutation in Neuroligin3 leads to the activation of the unfolded protein response in a PC12 Tet-On inducible systemen
dc.title.alternativeNeurolign 3 misfolding mutations and activation of the unfolded protein responseen
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from Portland Press via https://doi.org/http://dx.doi.org/10.1042/BJ20150274en
prism.endingPage434
prism.publicationDate2015en
prism.publicationNameBiochemical Journalen
prism.startingPage423
prism.volume473en
dc.rioxxterms.funderMRC
dc.rioxxterms.funderNIH
dc.rioxxterms.projectidG1002610
dc.rioxxterms.projectidMH092906
dcterms.dateAccepted2015-11-27en
rioxxterms.versionofrecord10.1042/BJ20150274en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2015-11-30en
dc.contributor.orcidMarciniak, Stefan [0000-0001-8472-7183]
dc.identifier.eissn1470-8728
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (G1002610)
pubs.funder-project-idAlpha One Foundation (unknown)
pubs.funder-project-idMRC (G0601840)
cam.orpheus.successThu Jan 30 12:55:26 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