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Cell Rep DOI:10.1016/j.celrep.2014.03.019

Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons.

Publication TypeJournal Article
Year of Publication2014
AuthorsWainger, BJ, Kiskinis, E, Mellin, C, Wiskow, O, Han, SSW, Sandoe, J, Perez, NP, Williams, LA, Lee, S, Boulting, G, Berry, JD, Brown, RH, Cudkowicz, ME, Bean, BP, Eggan, K, Woolf, CJ
JournalCell Rep
Volume7
Issue1
Pages1-11
Date Published2014 Apr 10
ISSN2211-1247
KeywordsAction Potentials, Amyotrophic Lateral Sclerosis, Cell Differentiation, Cells, Cultured, Gene Expression Regulation, Humans, Induced Pluripotent Stem Cells, Motor Neurons, Mutation, Patch-Clamp Techniques, Phenotype, Superoxide Dismutase, Superoxide Dismutase-1
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. 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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S2211-1247(14)00197-1
DOI10.1016/j.celrep.2014.03.019
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24703839?dopt=Abstract

Alternate JournalCell Rep
PubMed ID24703839
PubMed Central IDPMC4023477
Grant List2 R01 NS038153-15 / NS / NINDS NIH HHS / United States
RC2 NS069395 / NS / NINDS NIH HHS / United States
5 T32 GM007592-33 / GM / NIGMS NIH HHS / United States
1U24NS078736-01 / NS / NINDS NIH HHS / United States
RC2 NS070342 / NS / NINDS NIH HHS / United States
5 R01 NS038253-10 / NS / NINDS NIH HHS / United States
P30 HD018655 / HD / NICHD NIH HHS / United States
R01 NS036855 / NS / NINDS NIH HHS / United States
T32 GM007592 / GM / NIGMS NIH HHS / United States
R01 NS038253 / NS / NINDS NIH HHS / United States
RC2-NS070-342 / NS / NINDS NIH HHS / United States
1R01NS050557 / NS / NINDS NIH HHS / United States
K08 NS082364 / NS / NINDS NIH HHS / United States
U24 NS078736 / NS / NINDS NIH HHS / United States
R01 NS050557 / NS / NINDS NIH HHS / United States
5RC2NS069395-02 / NS / NINDS NIH HHS / United States