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SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits.

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cam.issuedOnline2017-07-05
dc.contributor.authorHautbergue, Guillaume M
dc.contributor.authorCastelli, Lydia M
dc.contributor.authorFerraiuolo, Laura
dc.contributor.authorSanchez-Martinez, Alvaro
dc.contributor.authorCooper-Knock, Johnathan
dc.contributor.authorHigginbottom, Adrian
dc.contributor.authorLin, Ya-Hui
dc.contributor.authorBauer, Claudia S
dc.contributor.authorDodd, Jennifer E
dc.contributor.authorMyszczynska, Monika A
dc.contributor.authorAlam, Sarah M
dc.contributor.authorGarneret, Pierre
dc.contributor.authorChandran, Jayanth S
dc.contributor.authorKaryka, Evangelia
dc.contributor.authorStopford, Matthew J
dc.contributor.authorSmith, Emma F
dc.contributor.authorKirby, Janine
dc.contributor.authorMeyer, Kathrin
dc.contributor.authorKaspar, Brian K
dc.contributor.authorIsaacs, Adrian M
dc.contributor.authorEl-Khamisy, Sherif F
dc.contributor.authorDe Vos, Kurt J
dc.contributor.authorNing, Ke
dc.contributor.authorAzzouz, Mimoun
dc.contributor.authorWhitworth, Alexander J
dc.contributor.authorShaw, Pamela J
dc.contributor.orcidWhitworth, Alex [0000-0002-1154-6629]
dc.date.accessioned2018-12-18T00:31:15Z
dc.date.accessioned2019-04-03T23:31:09Z
dc.date.available2018-12-18T00:31:15Z
dc.date.available2019-04-03T23:31:09Z
dc.date.issued2017-07-05
dc.description.abstractHexanucleotide repeat expansions in the C9ORF72 gene are the commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression of repeat transcripts and dipeptide repeat proteins trigger multiple mechanisms of neurotoxicity. How repeat transcripts get exported from the nucleus is unknown. Here, we show that depletion of the nuclear export adaptor SRSF1 prevents neurodegeneration and locomotor deficits in a Drosophila model of C9ORF72-related disease. This intervention suppresses cell death of patient-derived motor neuron and astrocytic-mediated neurotoxicity in co-culture assays. We further demonstrate that either depleting SRSF1 or preventing its interaction with NXF1 specifically inhibits the nuclear export of pathological C9ORF72 transcripts, the production of dipeptide-repeat proteins and alleviates neurotoxicity in Drosophila, patient-derived neurons and neuronal cell models. Taken together, we show that repeat RNA-sequestration of SRSF1 triggers the NXF1-dependent nuclear export of C9ORF72 transcripts retaining expanded hexanucleotide repeats and reveal a novel promising therapeutic target for neuroprotection.
dc.description.sponsorshipMRC, ERC, FP7
dc.identifier.doi10.17863/CAM.38291
dc.identifier.eissn2041-1723
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/291110
dc.languageeng
dc.language.isoeng
dc.publisherNature Publishing Group
dc.publisher.urlhttp://dx.doi.org/10.1038/ncomms16063
dc.relation.replaceshttps://www.repository.cam.ac.uk/handle/1810/287050
dc.relation.replaces1810/287050
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAdult
dc.subjectAged
dc.subjectAmyotrophic Lateral Sclerosis
dc.subjectAnimals
dc.subjectAstrocytes
dc.subjectC9orf72 Protein
dc.subjectCell Line
dc.subjectCoculture Techniques
dc.subjectDisease Models, Animal
dc.subjectDrosophila
dc.subjectFemale
dc.subjectFrontotemporal Dementia
dc.subjectHumans
dc.subjectMale
dc.subjectMice
dc.subjectMiddle Aged
dc.subjectNuclear Proteins
dc.subjectNucleocytoplasmic Transport Proteins
dc.subjectRNA-Binding Proteins
dc.subjectRats
dc.subjectSerine-Arginine Splicing Factors
dc.subjectTranscription Factors
dc.titleSRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits.
dc.typeArticle
dcterms.dateAccepted2017-05-24
prism.number16063
prism.publicationNameNature Communications
prism.volume8
pubs.funder-project-idMedical Research Council (MC_UU_00015/6)
pubs.funder-project-idMedical Research Council (MC_UP_1501/1)
pubs.funder-project-idEuropean Research Council (309742)
pubs.funder-project-idMedical Research Council (MC_UU_00015/7)
rioxxterms.licenseref.startdate2017-05-24
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/ncomms16063

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