肌萎缩侧索硬化症患者来源的运动神经元的内在膜兴奋性过高
Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons.
作者信息
Wainger Brian J, Kiskinis Evangelos, Mellin Cassidy, Wiskow Ole, Han Steve S W, Sandoe Jackson, Perez Numa P, Williams Luis A, Lee Seungkyu, Boulting Gabriella, Berry James D, Brown Robert H, Cudkowicz Merit E, Bean Bruce P, Eggan Kevin, Woolf Clifford J
机构信息
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.
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.
出版信息
Cell Rep. 2014 Apr 10;7(1):1-11. doi: 10.1016/j.celrep.2014.03.019. Epub 2014 Apr 3.
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.
肌萎缩侧索硬化症（ALS）是一种致命的运动神经系统神经退行性疾病。我们通过多电极阵列和膜片钳记录表明，在携带超氧化物歧化酶1（SOD1）、C9orf72和融合肉瘤突变的ALS患者的诱导多能干细胞衍生的运动神经元中，再现了ALS患者临床神经生理学研究检测到的过度兴奋。从基因校正但其他方面同基因的SOD1(+/+)干细胞系产生的运动神经元不表现出过度兴奋表型。与对照来源的运动神经元相比，SOD1(A4V/+) ALS患者来源的运动神经元延迟整流钾电流幅度降低，这一缺陷可能是其过度兴奋的基础。当在SOD1突变的ALS病例中进行测试时，Kv7通道激活剂瑞替加滨既能阻断过度兴奋，又能改善运动神经元在体外的存活。因此，人类干细胞衍生神经元的电生理特征可以揭示疾病相关机制并识别治疗候选物。
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