title: Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability.
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.
authors.affiliation: 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.
authors.forename: Anna-Claire
authors.initials: AC
authors.lastname: Devlin
authors.affiliation: 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.
authors.forename: Karen
authors.initials: K
authors.lastname: Burr
authors.affiliation: 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.
authors.forename: Shyamanga
authors.initials: S
authors.lastname: Borooah
authors.affiliation: School of Psychology and Neuroscience, University of St. Andrews, Westburn Lane, St. Andrews KY16 9JP, UK.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Foster
authors.affiliation: 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.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Cleary
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Imbisaat
authors.initials: I
authors.lastname: Geti
authors.affiliation: Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, Department of Surgery, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Vallier
authors.affiliation: MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: 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.
authors.forename: Siddharthan
authors.initials: S
authors.lastname: Chandran
authors.affiliation: 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.
authors.forename: Gareth B
authors.initials: GB
authors.lastname: Miles
mesh_terms: D000200:Action Potentials; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000073885:C9orf72 Protein; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D008297:Male; D009046:Motor Neurons / Q000473:pathology; D009154:Mutation; D016366:Open Reading Frames; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000737:chemistry; D011506:Proteins / Q000235:genetics*; D012964:Sodium / Q000737:chemistry
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; C000598624:TARDBP protein, human; D012964:Sodium; D011188:Potassium