Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability

Anna-Claire Devlin, Karen Burr, Shyamanga Borooah, Joshua D. Foster, Elaine M. Cleary, Imbisaat Geti, Ludovic Vallier, Christopher E. Shaw, Siddharthan Chandran and Gareth B. Miles ()
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Anna-Claire Devlin: School of Psychology and Neuroscience, University of St. Andrews, Westburn Lane, St. Andrews KY16 9JP, UK
Karen Burr: Euan MacDonald Centre for Motor Neurone Disease Research
Shyamanga Borooah: Euan MacDonald Centre for Motor Neurone Disease Research
Joshua D. Foster: School of Psychology and Neuroscience, University of St. Andrews, Westburn Lane, St. Andrews KY16 9JP, UK
Elaine M. Cleary: Euan MacDonald Centre for Motor Neurone Disease Research
Imbisaat Geti: Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge
Ludovic Vallier: Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge
Christopher E. Shaw: MRC Centre for Neurodegeneration Research, King’s College London, Institute of Psychiatry
Siddharthan Chandran: Euan MacDonald Centre for Motor Neurone Disease Research
Gareth B. Miles: School of Psychology and Neuroscience, University of St. Andrews, Westburn Lane, St. Andrews KY16 9JP, UK

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms6999

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