title: INaP selective inhibition reverts precocious inter- and motorneurons hyperexcitability in the Sod1-G93R zebrafish ALS model.
abstract: The pathogenic role of SOD1 mutations in amyotrophic lateral sclerosis (ALS) was investigated using a zebrafish disease model stably expressing the ALS-linked G93R mutation. In addition to the main pathological features of ALS shown by adult fish, we found remarkably precocious alterations in the development of motor nerve circuitry and embryo behavior, and suggest that these alterations are prompted by interneuron and motor neuron hyperexcitability triggered by anomalies in the persistent pacemaker sodium current INaP. The riluzole-induced modulation of INaP reduced spinal neuron excitability, reverted the behavioral phenotypes and improved the deficits in motor nerve circuitry development, thus shedding new light on the use of riluzole in the management of ALS. Our findings provide a valid phenotype-based tool for unbiased in vivo drug screening that can be used to develop new therapies.
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, Neuroscience Institute, National Research Council (CNR), Via Vanvitelli 32, 20139 Milano, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Benedetti
authors.affiliation: Department of BioSciences, University of Milan, Via Celoria 26, 20133 Milano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ghilardi
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, Neuroscience Institute, National Research Council (CNR), Via Vanvitelli 32, 20139 Milano, Italy.
authors.forename: Elsa
authors.initials: E
authors.lastname: Rottoli
authors.affiliation: Department of Veterinary Science and Public Health, University of Milan, Via Celoria 10, 20133 Milano, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: De Maglie
authors.affiliation: Department of BioSciences, University of Milan, Via Celoria 26, 20133 Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Prosperi
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Trentacoste 2, 20133 Milano, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Perego
authors.affiliation: Department of BioSciences, University of Milan, Via Celoria 26, 20133 Milano, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Baruscotti
authors.affiliation: Department of BioSciences, University of Milan, Via Celoria 26, 20133 Milano, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Bucchi
authors.affiliation: Department of BioSciences, University of Milan, Via Celoria 26, 20133 Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Del Giacco
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, Neuroscience Institute, National Research Council (CNR), Via Vanvitelli 32, 20139 Milano, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Francolini
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D015870:Gene Expression; D008124:Locomotion; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology*; D009132:Muscles / Q000473:pathology; D009154:Mutation; D009469:Neuromuscular Junction / Q000378:metabolism; D010641:Phenotype; D010658:Phenylglyoxal / Q000031:analogs & derivatives* / Q000494:pharmacology; D019782:Riluzole / Q000494:pharmacology; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D015027:Zebrafish
chemical_list: C057115:isonitrosoacetophenone; D019782:Riluzole; D013482:Superoxide Dismutase; D010658:Phenylglyoxal