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dc.contributor.authorBurley, Sarah
dc.contributor.authorBeccano-Kelly, Dayne A.
dc.contributor.authorTalbot, Kevin
dc.contributor.authorCordero Llana, Oscar
dc.contributor.authorWade-Martins, Richard
dc.identifier.citationBurley , S , Beccano-Kelly , D A , Talbot , K , Cordero Llana , O & Wade-Martins , R 2022 , ' Hyperexcitability in young iPSC-derived C9ORF72 mutant motor neurons is associated with increased intracellular calcium release ' , Scientific Reports , vol. 12 , 7378 .
dc.identifier.otherPURE: 279514738
dc.identifier.otherPURE UUID: 51e685dd-ebf4-4f87-b6f0-0eaff9075d67
dc.identifier.otherJisc: 295696
dc.identifier.otherpublisher-id: s41598-022-09751-3
dc.identifier.othermanuscript: 9751
dc.identifier.otherScopus: 85129370710
dc.identifier.otherWOS: 000791506100020
dc.descriptionS.B. was supported by a Motor Neuron Disease Association studentship (WadeMartins/Oct13/867-792) and D.A.B was supported by the Monument Trust Discovery Award (J-1403) from Parkinson’s UK. The work was supported by the Medical Research Council Dementias Platform UK Stem Cell Network (Grant MR/M024962/1 to RW-M).en
dc.description.abstractA large hexanucleotide repeat expansion in the C9ORF72 gene is the most prevalent cause of amyotrophic lateral sclerosis (ALS). To better understand neuronal dysfunction during ALS progression, we studied motor neuron (MN) cultures derived from iPSC lines generated from C9ORF72 (C9) expansion carriers and unaffected controls. C9 and control MN cultures showed comparable mRNA levels for MN markers SMI-32, HB9 and ISL1 and similar MN yields (> 50% TUJ1/SMI-32 double-positive MNs). Using whole-cell patch clamp we showed that C9-MNs have normal membrane capacitance, resistance and resting potential. However, immature (day 40) C9-MNs exhibited a hyperexcitable phenotype concurrent with increased release of calcium (Ca2+) from internal stores, but with no changes to NaV and KV currents. Interestingly, this was a transient phenotype. By day 47, maturing C9-MNs demonstrated normal electrophysiological activity, displaying only subtle alterations on mitochondrial Ca2+ release. Together, these findings suggest the potential importance of a developmental component to C9ORF72-related ALS.
dc.relation.ispartofScientific Reportsen
dc.rightsCopyright © The Author(s) 2022. 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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.en
dc.subjectQH426 Geneticsen
dc.subjectQP Physiologyen
dc.subjectRC0321 Neuroscience. Biological psychiatry. Neuropsychiatryen
dc.titleHyperexcitability in young iPSC-derived C9ORF72 mutant motor neurons is associated with increased intracellular calcium releaseen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Biologyen
dc.description.statusPeer revieweden

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