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dc.contributor.authorThangaraj Selvaraj , Bhuvaneish
dc.contributor.authorLivesey , Matthew
dc.contributor.authorZhao , Chen
dc.contributor.authorGregory , Jenna
dc.contributor.authorJames, Owain
dc.contributor.authorCleary, Elaine
dc.contributor.authorChouhan, Amit Kumar
dc.contributor.authorGane, Angus
dc.contributor.authorPerkins, Emma
dc.contributor.authorDando, Owen
dc.contributor.authorLillico, Simon
dc.contributor.authorLee, Youn-Bok
dc.contributor.authorNishimura, Agnes
dc.contributor.authorPoreci, Urjana
dc.contributor.authorThankamony, Sai
dc.contributor.authorPray, Meryll
dc.contributor.authorVasistha, Navneet
dc.contributor.authorMagnani, Dario
dc.contributor.authorBorooah, Shyamanga
dc.contributor.authorBurr, Karen
dc.contributor.authorStory, David
dc.contributor.authorMcCampbell, Alexander
dc.contributor.authorShaw, Christopher
dc.contributor.authorKind, Peter
dc.contributor.authorAitman, Timothy J.
dc.contributor.authorWhitelaw, Bruce
dc.contributor.authorWilmut, Ian
dc.contributor.authorSmith, Colin
dc.contributor.authorMiles, Gareth B.
dc.contributor.authorHardingham, Giles
dc.contributor.authorWyllie, David
dc.contributor.authorChandran, Siddharthan
dc.identifier.citationThangaraj Selvaraj , B , Livesey , M , Zhao , C , Gregory , J , James , O , Cleary , E , Chouhan , A K , Gane , A , Perkins , E , Dando , O , Lillico , S , Lee , Y-B , Nishimura , A , Poreci , U , Thankamony , S , Pray , M , Vasistha , N , Magnani , D , Borooah , S , Burr , K , Story , D , McCampbell , A , Shaw , C , Kind , P , Aitman , T J , Whitelaw , B , Wilmut , I , Smith , C , Miles , G B , Hardingham , G , Wyllie , D & Chandran , S 2018 , ' C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca 2+ -permeable AMPA receptor-mediated excitotoxicity ' , Nature Communications , vol. 9 , 347 .
dc.identifier.otherPURE: 251810863
dc.identifier.otherPURE UUID: 705fda59-644f-4d57-9580-94959caf7359
dc.identifier.otherScopus: 85041044335
dc.identifier.otherORCID: /0000-0002-8624-4625/work/41026487
dc.identifier.otherWOS: 000423155700005
dc.descriptionFunded by The Wellcome Trust (Grant 092742/Z/10/Z), MNDA (Miles/Oct14/878-792), MRC, Euan MacDonald Centre, UK DRI, DBT-India, ISSF (WT/UoE), Royal Society of Edinburgh (CRF), and Biogen/UoE Joint Discovery Research Collaboration. RNA-Seq raw reads were generated by Edinburgh Genomics, The University of Edinburgh. Edinburgh Genomics is partly supported through core grants from NERC (R8/H10/56), MRC (MR/K001744/1), and BBSRC (BB/J004243/1).en
dc.description.abstractMutations in C9ORF72 are the most common cause of familial amyotrophic lateral sclerosis (ALS). Here, through a combination of RNA-seq and electrophysiological studies on induced pluripotent stem cell (iPSC) derived motor neuron (MNs), we show that increased expression of GluA1 AMPA receptor (AMPAR) subunit occurs in MNs with C9ORF72 mutations that leads to increased Ca2+-permeable AMPAR expression and results in enhanced selective MN vulnerability to excitotoxicity. These deficits are not found in iPSC-derived cortical neurons and are abolished by CRISPR/Cas9-mediated correction of the C9ORF72 repeat expansion in MNs. We also demonstrate that MN-specific dysregulation of AMPAR expression is also present in C9ORF72 patient post mortem material. We therefore present multiple lines of evidence for the specific upregulation of GluA1 subunits in human mutant C9ORF72 MNs that could lead to a potential pathogenic excitotoxic mechanism in ALS.
dc.relation.ispartofNature Communicationsen
dc.rights© The Author(s) 2018. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit
dc.subjectRC0321 Neuroscience. Biological psychiatry. Neuropsychiatryen
dc.titleC9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicityen
dc.typeJournal articleen
dc.contributor.sponsorMotor Neurone Disease Associationen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Psychology and Neuroscienceen
dc.contributor.institutionUniversity of St Andrews. Institute of Behavioural and Neural Sciencesen
dc.description.statusPeer revieweden

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