Journal
CELL REPORTS
Volume 7, Issue 1, Pages 1-11Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.03.019
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Funding
- NIH [5 T32 GM007592-33, 5 R01 NS038253-10, 2 R01 NS038153-15]
- Harvard NeuroDiscovery
- ALS Association
- American Brain Foundation Clinical Research Fellowship
- Charles King Trust Postdoctoral Fellowship
- American Brain Foundation/ALS Association
- KL2 MeRIT fellowship/Harvard Catalyst
- ALS Therapy Alliance
- P2ALS
- Angel Fund
- Pierre L. de Bourgknecht ALS Research Foundation
- Al-Athel ALS Research Foundation
- ALS Family Charitable Foundation
- NIH/NINDS [1R01NS050557]
- NIH/NINDS (NINDS ARRA Award) [RC2-NS070342]
- Project ALS
- Target ALS
- NINDS GO grant [5RC2NS069395-02]
- NINDS R24 [1U24NS078736-01]
- HHMI
- New York Stem Cell Foundation
- GlaxoSmithKline
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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.
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