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

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  • Anna-Claire Devlin

    (School of Psychology and Neuroscience, University of St. Andrews, Westburn Lane, St. Andrews KY16 9JP, UK
    Euan MacDonald Centre for Motor Neurone Disease Research)

  • Karen Burr

    (Euan MacDonald Centre for Motor Neurone Disease Research
    Centre for Neuroregeneration and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh)

  • Shyamanga Borooah

    (Euan MacDonald Centre for Motor Neurone Disease Research
    Centre for Neuroregeneration and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh)

  • 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
    Centre for Neuroregeneration and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh)

  • 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
    Centre for Neuroregeneration and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh)

  • Gareth B. Miles

    (School of Psychology and Neuroscience, University of St. Andrews, Westburn Lane, St. Andrews KY16 9JP, UK
    Euan MacDonald Centre for Motor Neurone Disease Research)

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.

Suggested Citation

  • Anna-Claire Devlin & Karen Burr & Shyamanga Borooah & Joshua D. Foster & Elaine M. Cleary & Imbisaat Geti & Ludovic Vallier & Christopher E. Shaw & Siddharthan Chandran & Gareth B. Miles, 2015. "Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms6999
    DOI: 10.1038/ncomms6999
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