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

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

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...

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Main Authors: 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
Format: Article
Language:English
Published: Elsevier 2014-04-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124714001971
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spelling doaj-112c904730ec41668ec020f0d2182e622020-11-24T20:58:22ZengElsevierCell Reports2211-12472014-04-017111110.1016/j.celrep.2014.03.019Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor NeuronsBrian J. Wainger0Evangelos Kiskinis1Cassidy Mellin2Ole Wiskow3Steve S.W. Han4Jackson Sandoe5Numa P. Perez6Luis A. Williams7Seungkyu Lee8Gabriella Boulting9James D. Berry10Robert H. Brown Jr.11Merit E. Cudkowicz12Bruce P. Bean13Kevin Eggan14Clifford J. Woolf15FM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USAHarvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USAFM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USAHarvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USAHarvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USAHarvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USAFM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USAHarvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USAFM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USAHarvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USADepartment of Neurology, Massachusetts General Hospital, Boston, MA 02114, USADepartment of Neurology, University of Massachusetts Medical Center, Worcester, MA 01655, USADepartment of Neurology, Massachusetts General Hospital, Boston, MA 02114, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USAHarvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University and the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02138, USAFM Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USAAmyotrophic 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.http://www.sciencedirect.com/science/article/pii/S2211124714001971
collection DOAJ
language English
format Article
sources DOAJ
author 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
spellingShingle 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
Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons
Cell Reports
author_facet 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
author_sort Brian J. Wainger
title Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons
title_short Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons
title_full Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons
title_fullStr Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons
title_full_unstemmed Intrinsic Membrane Hyperexcitability of Amyotrophic Lateral Sclerosis Patient-Derived Motor Neurons
title_sort intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2014-04-01
description 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.
url http://www.sciencedirect.com/science/article/pii/S2211124714001971
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