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

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

Author information

1
Department of Neurology, Hannover Medical School, Hannover, Germany.
2
Molecular Neurobiology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA.
3
Division for Neurodegenerative Diseases, Department of Neurology, Dresden University of Technology, Dresden, Germany.
4
DFG Research Center for Regenerative Therapies (CRTD), Technische Universität Dresden, Dresden, Germany.
5
German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.
6
Department of Neurology, University of Rostock, Rostock, Germany.
7
Max-Planck-Institute for Molecular Biomedicine, Münster, Germany.
8
Institute of Anatomy and Cell Biology, Ulm University, Ulm, Germany.
9
Institute of Neuroanatomy, Eberhard Karls University Tübingen, Tübingen, Germany.
10
Department of Neurology, Ulm University, Ulm, Germany.

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.

KEYWORDS:

4-Aminopyridine; Amyotrophic lateral sclerosis; Hypoexcitability; Induced pluripotent stem cells; Motor neurons

PMID:
26946488
DOI:
10.1002/stem.2354
[Indexed for MEDLINE]
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