@article{594e5fcb313449afaff3fbf5545311c6,
title = "Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons",
abstract = "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 invitro 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.",
author = "Wainger, {Brian J.} and Evangelos Kiskinis and Cassidy Mellin and Ole Wiskow and Han, {Steve S W} and Jackson Sandoe and Perez, {Numa P.} and Williams, {Luis A.} and Seungkyu Lee and Gabriella Boulting and Berry, {James D.} and Brown, {Robert H.} and Cudkowicz, {Merit E.} and Bean, {Bruce P.} and Kevin Eggan and Woolf, {Clifford J.}",
note = "Funding Information: We thank W. David and S. Cash for comments, suggestions, and review of the manuscript, K. Kapur for assistance with statistical analysis, and K. Wainger for assistance with figures. This work was supported by NIH 5 T32 GM007592-33, Harvard NeuroDiscovery, ALS Association, and American Brain Foundation Clinical Research Fellowship (B.J.W.); Charles King Trust Postdoctoral Fellowship (E.K.); American Brain Foundation/ALS Association and KL2 MeRIT fellowship/Harvard Catalyst (S.S.W.H.); ALS Therapy Alliance, P2ALS, Angel Fund, Pierre L. de Bourgknecht ALS Research Foundation, Al-Athel ALS Research Foundation, ALS Family Charitable Foundation and NIH/NINDS (1R01NS050557 and NINDS ARRA Award RC2-NS070-342) (R.H.B.); P2ALS, Project ALS, Target ALS, NINDS GO grant (5RC2NS069395-02), NINDS R24 (1U24NS078736-01) and HHMI (K.E.); NIH (5 R01 NS038253-10; 2 R01 NS038153-15), Target ALS and New York Stem Cell Foundation (C.J.W.). GlaxoSmithKline supports research distinct from this study as part of an alliance with the Harvard Stem Cell Institute, including the Woolf and Eggan labs. ",
year = "2014",
month = oct,
day = "4",
doi = "10.1016/j.celrep.2014.03.019",
language = "English (US)",
volume = "7",
pages = "1--11",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}