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

Cell Rep
Authors
Keywords
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.

Year of Publication
2014
Journal
Cell Rep
Volume
7
Issue
1
Pages
1-11
Date Published
2014 Apr 10
ISSN
2211-1247
URL
DOI
10.1016/j.celrep.2014.03.019
PubMed ID
24703839
PubMed Central ID
PMC4023477
Links
Grant list
2 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