Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability
MetadataShow full item record
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which a greater understanding of early disease mechanisms is needed to reveal novel therapeutic targets. We report the use of human induced pluripotent stem cell (iPSC)-derived motoneurons (MNs) to study the pathophysiology of ALS. We demonstrate that MNs derived from iPSCs obtained from healthy individuals or patients harbouring TARDBP or C9ORF72 ALS-causing mutations are able to develop appropriate physiological properties. However, patient iPSC-derived MNs, independent of genotype, display an initial hyperexcitability followed by progressive loss of action potential output and synaptic activity. This loss of functional output reflects a progressive decrease in voltage-activated Na+ and K+ currents, which occurs in the absence of overt changes in cell viability. These data implicate early dysfunction or loss of ion channels as a convergent point that may contribute to the initiation of downstream degenerative pathways that ultimately lead to MN loss in ALS.
Devlin , A-C , Burr , K , Borooah , S , Foster , J D , Cleary , E M , Geti , I , Vallier , L , Shaw , C E , Chandran , S & Miles , G B 2015 , ' Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability ' Nature Communications , vol 6 , 5999 . DOI: 10.1038/ncomms6999
Copyright 2015 Macmillan Publishers Limited. All rights reserved. This 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/
This work has been supported by: Motor Neurone Disease Association (G.B.M., S.C. and C.E.S.); Euan MacDonald Centre (G.B.M. and S.C.); European Research Council (L.V.); Cambridge Hospitals National Institute for Health Research Biomedical Research Center (L.V.).
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.