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-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. SOD1(A4V/+) 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.
FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Brian J
BJ
Wainger
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.
Evangelos
E
Kiskinis
FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA.
Cassidy
C
Mellin
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.
Ole
O
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; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
Steve S W
SS
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
J
Sandoe
FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA.
Numa P
NP
Perez
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.
Luis A
LA
Williams
FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA.
Seungkyu
S
Lee
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.
Gabriella
G
Boulting
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
James D
JD
Berry
Department of Neurology, University of Massachusetts Medical Center, Worcester, MA 01655, USA.
Robert H
RH
Brown
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
Merit E
ME
Cudkowicz
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Bruce P
BP
Bean
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; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA; The Howard Hughes Medical Institute. Electronic address: eggan@mcb.harvard.edu.
Kevin
K
Eggan
FM Kirby Neurobiology Center, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: clifford.woolf@childrens.harvard.edu.
Clifford J
CJ
Woolf
D000200:Action Potentials / Q000502:physiology; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology; D009046:Motor Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D018408:Patch-Clamp Techniques; D010641:Phenotype; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1