4-氨基吡啶诱导的活性挽救了来自肌萎缩侧索硬化症患者诱导多能干细胞的低兴奋性运动神经元。

4-Aminopyridine Induced Activity Rescues Hypoexcitable Motor Neurons from Amyotrophic Lateral Sclerosis Patient-Derived Induced Pluripotent Stem Cells.

作者信息

Naujock Maximilian, Stanslowsky Nancy, Bufler Sebastian, Naumann Marcel, Reinhardt Peter, Sterneckert Jared, Kefalakes Ekaterini, Kassebaum Carola, Bursch Franziska, Lojewski Xenia, Storch Alexander, Frickenhaus Marie, Boeckers Tobias M, Putz Stefan, Demestre Maria, Liebau Stefan, Klingenstein Moritz, Ludolph Albert C, Dengler Reinhard, Kim Kwang-Soo, Hermann Andreas, Wegner Florian, Petri Susanne

机构信息

Department of Neurology, Hannover Medical School, Hannover, Germany.

Molecular Neurobiology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA.

出版信息

Stem Cells. 2016 Jun;34(6):1563-75. doi: 10.1002/stem.2354. Epub 2016 Mar 28.

DOI:10.1002/stem.2354

PMID:26946488

Abstract

Despite decades of research on amyotrophic lateral sclerosis (ALS), there is only one approved drug, which minimally extends patient survival. Here, we investigated pathophysiological mechanisms underlying ALS using motor neurons (MNs) differentiated from induced pluripotent stem cells (iPSCs) derived from ALS patients carrying mutations in FUS or SOD1. Patient-derived MNs were less active and excitable compared to healthy controls, due to reduced Na(+) /K(+) ratios in both ALS groups accompanied by elevated potassium channel (FUS) and attenuated sodium channel expression levels (FUS, SOD1). ALS iPSC-derived MNs showed elevated endoplasmic reticulum stress (ER) levels and increased caspase activation. Treatment with the FDA approved drug 4-Aminopyridine (4AP) restored ion-channel imbalances, increased neuronal activity levels and decreased ER stress and caspase activation. This study provides novel pathophysiological data, including a mechanistic explanation for the observed hypoexcitability in patient-derived MNs and a new therapeutic strategy to provide neuroprotection in MNs affected by ALS. Stem Cells 2016;34:1563-1575.

摘要

尽管对肌萎缩侧索硬化症（ALS）进行了数十年的研究，但目前只有一种获批药物，它只能在极小程度上延长患者生存期。在此，我们利用从携带FUS或SOD1突变的ALS患者诱导多能干细胞（iPSC）分化而来的运动神经元（MN），研究了ALS潜在的病理生理机制。与健康对照相比，源自患者的MN活性和兴奋性较低，这是由于两个ALS组中的Na(+) /K(+) 比率降低，同时伴有钾通道升高（FUS）和钠通道表达水平减弱（FUS、SOD1）。源自ALS患者iPSC的MN显示内质网应激（ER）水平升高且半胱天冬酶激活增加。使用美国食品药品监督管理局（FDA）批准的药物4-氨基吡啶（4AP）进行治疗可恢复离子通道失衡，提高神经元活性水平，并降低ER应激和半胱天冬酶激活。本研究提供了新的病理生理数据，包括对源自患者的MN中观察到的兴奋性降低的机制解释，以及为受ALS影响的MN提供神经保护的新治疗策略。《干细胞》2016年；34:1563 - 1575。