Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons

Brian J. Wainger; Evangelos Kiskinis; Cassidy Mellin; Ole Wiskow; Steve S.W. Han; Jackson Sandoe; Numa P. Perez; Luis A. Williams; Seungkyu Lee; Gabriella Boulting; James D. Berry; Robert H. Brown Jr.; Merit E. Cudkowicz; Bruce P. Bean; Kevin Eggan; Clifford J. Woolf

doi:10.1016/j.celrep.2014.03.019

Cell Reports (Apr 2014)

Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons

Brian J. Wainger,
Evangelos Kiskinis,
Cassidy Mellin,
Ole Wiskow,
Steve S.W. Han,
Jackson Sandoe,
Numa P. Perez,
Luis A. Williams,
Seungkyu Lee,
Gabriella Boulting,
James D. Berry,
Robert H. Brown Jr.,
Merit E. Cudkowicz,
Bruce P. Bean,
Kevin Eggan,
Clifford J. Woolf

Affiliations

Brian J. Wainger: FM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA
Evangelos Kiskinis: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
Cassidy Mellin: FM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA
Ole Wiskow: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
Steve S.W. Han: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
Jackson Sandoe: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
Numa P. Perez: FM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA
Luis A. Williams: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
Seungkyu Lee: FM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA
Gabriella Boulting: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
James D. Berry: Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
Robert H. Brown Jr.: Department of Neurology, University of Massachusetts Medical Center, Worcester, MA 01655, USA
Merit E. Cudkowicz: Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
Bruce P. Bean: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
Kevin Eggan: Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USA
Clifford J. Woolf: FM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA

DOI: https://doi.org/10.1016/j.celrep.2014.03.019
Journal volume & issue: Vol. 7, no. 1
pp. 1 – 11

Abstract

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor nervous system. We show using multielectrode array and patch-clamp recordings that hyperexcitability detected by clinical neurophysiological studies of ALS patients is recapitulated in induced pluripotent stem cell-derived motor neurons from ALS patients harboring superoxide dismutase 1 (SOD1), C9orf72, and fused-in-sarcoma mutations. Motor neurons produced from a genetically corrected but otherwise isogenic SOD1+/+ stem cell line do not display the hyperexcitability phenotype. SOD1A4V/+ ALS patient-derived motor neurons have reduced delayed-rectifier potassium current amplitudes relative to control-derived motor neurons, a deficit that may underlie their hyperexcitability. The Kv7 channel activator retigabine both blocks the hyperexcitability and improves motor neuron survival in vitro when tested in SOD1 mutant ALS cases. Therefore, electrophysiological characterization of human stem cell-derived neurons can reveal disease-related mechanisms and identify therapeutic candidates.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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