RNA sequencing of synaptic and cytoplasmic Upf1-bound transcripts supports contribution of nonsense-mediated decay to epileptogenesis

DC FieldValueLanguage
dc.contributor.authorMooney, Claire-
dc.contributor.authorJimenez-Mateos, Eva M.-
dc.contributor.authorEngel, Tobias-
dc.contributor.authorMooney, Catherine-
dc.contributor.authoret al.-
dc.date.accessioned2019-04-23T08:38:44Z-
dc.date.available2019-04-23T08:38:44Z-
dc.date.copyright2017 the Authorsen_US
dc.date.issued2017-01-27-
dc.identifier.citationScientific Reportsen_US
dc.identifier.issn2045-2322-
dc.identifier.urihttp://hdl.handle.net/10197/10063-
dc.description.abstractThe nonsense mediated decay (NMD) pathway is a critical surveillance mechanism for identifying aberrant mRNA transcripts. It is unknown, however, whether the NMD system is affected by seizures in vivo and whether changes confer beneficial or maladaptive responses that influence long-term outcomes such the network alterations that produce spontaneous recurrent seizures. Here we explored the responses of the NMD pathway to prolonged seizures (status epilepticus) and investigated the effects of NMD inhibition on epilepsy in mice. Status epilepticus led to increased protein levels of Up-frameshift suppressor 1 homolog (Upf1) within the mouse hippocampus. Upf1 protein levels were also higher in resected hippocampus from patients with intractable temporal lobe epilepsy. Immunoprecipitation of Upf1-bound RNA from the cytoplasmic and synaptosomal compartments followed by RNA sequencing identified unique populations of NMD-associated transcripts and altered levels after status epilepticus, including known substrates such as Arc as well as novel targets including Inhba and Npas4. Finally, long-term video-EEG recordings determined that pharmacologic interference in the NMD pathway after status epilepticus reduced the later occurrence of spontaneous seizures in mice. These findings suggest compartment-specific recruitment and differential loading of transcripts by NMD pathway components may contribute to the process of epileptogenesis.en_US
dc.description.sponsorshipEuropean Commission - Seventh Framework Programme (FP7)en_US
dc.description.sponsorshipHigher Education Authorityen_US
dc.description.sponsorshipScience Foundation Irelanden_US
dc.language.isoenen_US
dc.publisherSpringeren_US
dc.rightsThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/en_US
dc.subjectNonsense mediated decay (NMD) pathwayen_US
dc.subjectmRNA transcriptsen_US
dc.subjectStatus epilepticusen_US
dc.subjectNMD inhibitionen_US
dc.subjectEpileptogenesisen_US
dc.titleRNA sequencing of synaptic and cytoplasmic Upf1-bound transcripts supports contribution of nonsense-mediated decay to epileptogenesisen_US
dc.typeJournal Articleen_US
dc.internal.authorcontactothercatherine.mooney@ucd.ieen_US
dc.statusPeer revieweden_US
dc.identifier.volume7en_US
dc.identifier.issue41517en_US
dc.identifier.doi10.1038/srep41517-
dc.neeo.contributorMooney|Claire|aut|-
dc.neeo.contributorJimenez-Mateos|Eva M.|aut|-
dc.neeo.contributorEngel|Tobias|aut|-
dc.neeo.contributorMooney|Catherine|aut|-
dc.neeo.contributoret al.||aut|-
dc.date.updated2018-07-21T21:49:43Z-
dc.identifier.grantid08/IN1/B1875-
dc.identifier.grantid13/IA/1891-
dc.identifier.grantid14/ADV/RC2721-
dc.identifier.grantid602130-
item.fulltextWith Fulltext-
item.grantfulltextopen-
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