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Nat Commun. 2015 Jan 12;6:5999. doi: 10.1038/ncomms6999.

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

Author information

1
1] School of Psychology and Neuroscience, University of St. Andrews, Westburn Lane, St. Andrews KY16 9JP, UK [2] Euan MacDonald Centre for Motor Neurone Disease Research, Edinburgh EH16 4SB, UK.
2
1] Euan MacDonald Centre for Motor Neurone Disease Research, Edinburgh EH16 4SB, UK [2] Centre for Neuroregeneration and Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
3
School of Psychology and Neuroscience, University of St. Andrews, Westburn Lane, St. Andrews KY16 9JP, UK.
4
Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge CB2 0XY, UK.
5
MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK.

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.

PMID:
25580746
PMCID:
PMC4338554
DOI:
10.1038/ncomms6999
[Indexed for MEDLINE]
Free PMC Article

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