title: 4-Aminopyridine Induced Activity Rescues Hypoexcitable Motor Neurons from Amyotrophic Lateral Sclerosis Patient-Derived Induced Pluripotent Stem Cells.
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.
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.|Molecular Neurobiology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Naujock
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Nancy
authors.initials: N
authors.lastname: Stanslowsky
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bufler
authors.affiliation: Division for Neurodegenerative Diseases, Department of Neurology, Dresden University of Technology, Dresden, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Naumann
authors.affiliation: DFG Research Center for Regenerative Therapies (CRTD), Technische Universität Dresden, Dresden, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Reinhardt
authors.affiliation: DFG Research Center for Regenerative Therapies (CRTD), Technische Universität Dresden, Dresden, Germany.
authors.forename: Jared
authors.initials: J
authors.lastname: Sterneckert
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Kefalakes
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Kassebaum
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Bursch
authors.affiliation: Division for Neurodegenerative Diseases, Department of Neurology, Dresden University of Technology, Dresden, Germany.
authors.forename: Xenia
authors.initials: X
authors.lastname: Lojewski
authors.affiliation: Division for Neurodegenerative Diseases, Department of Neurology, Dresden University of Technology, Dresden, Germany.|DFG Research Center for Regenerative Therapies (CRTD), Technische Universität Dresden, Dresden, Germany.|German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.|Department of Neurology, University of Rostock, Rostock, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Storch
authors.affiliation: Max-Planck-Institute for Molecular Biomedicine, Münster, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Frickenhaus
authors.affiliation: Institute of Anatomy and Cell Biology, Ulm University, Ulm, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.affiliation: Institute of Anatomy and Cell Biology, Ulm University, Ulm, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Putz
authors.affiliation: Institute of Anatomy and Cell Biology, Ulm University, Ulm, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Demestre
authors.affiliation: Institute of Neuroanatomy, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebau
authors.affiliation: Institute of Neuroanatomy, Eberhard Karls University Tübingen, Tübingen, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Klingenstein
authors.affiliation: Department of Neurology, Ulm University, Ulm, Germany.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dengler
authors.affiliation: Molecular Neurobiology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA.
authors.forename: Kwang-Soo
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Division for Neurodegenerative Diseases, Department of Neurology, Dresden University of Technology, Dresden, Germany.|German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermann
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wegner
authors.affiliation: Department of Neurology, Hannover Medical School, Hannover, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Petri
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology*; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D000066829:Neuroprotection / Q000187:drug effects; D010641:Phenotype; D034702:RNA-Binding Protein FUS / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: C000599550:FUS protein, human; D007473:Ion Channels; D034702:RNA-Binding Protein FUS; D015761:4-Aminopyridine; D013482:Superoxide Dismutase; D020169:Caspases
keywords: 4-Aminopyridine; Amyotrophic lateral sclerosis; Hypoexcitability; Induced pluripotent stem cells; Motor neurons