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, Gareth B. Miles*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

206 Citations (Scopus)
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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 absenceof 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.

Original languageEnglish
Article number5999
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 12 Jan 2015

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