title: Mutant SOD1 protein increases Nav1.3 channel excitability.
abstract: Amyotrophic lateral sclerosis (ALS) is a lethal paralytic disease caused by the degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Mutations in the gene encoding copper/zinc superoxide dismutase (SOD1) are present in ~20% of familial ALS and ~2% of all ALS cases. The most common SOD1 gene mutation in North America is a missense mutation substituting valine for alanine (A4V). In this study, we analyze sodium channel currents in oocytes expressing either wild-type or mutant (A4V) SOD1 protein. We demonstrate that the A4V mutation confers a propensity to hyperexcitability on a voltage-dependent sodium channel (Nav1.3) mediated by heightened total Na(+) conductance and a hyperpolarizing shift in the voltage dependence of Nav1.3 activation. To estimate the impact of these channel effects on excitability in an intact neuron, we simulated these changes in the program NEURON; this shows that the changes induced by mutant SOD1 increase the spontaneous firing frequency of the simulated neuron. These findings are consistent with the view that excessive excitability of neurons is one component in the pathogenesis of this disease.
authors.affiliation: Institute of Biomedical Engineering, Boğaziçi University, Istanbul, Turkey. kubatelif@gmail.com.|REMER (Regenerative and Restorative Medicine Research Center), Istanbul Medipol University, Istanbul, Turkey. kubatelif@gmail.com.
authors.forename: Elif
authors.initials: E
authors.lastname: Kubat Öktem
authors.affiliation: Departments of Chemical and Systems Biology and Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Mruk
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Medical Engineering, Acıbadem University, Istanbul, Turkey.
authors.forename: Ata
authors.initials: A
authors.lastname: Akin
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Kobertz
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D000818:Animals; D055724:Electrophysiological Phenomena / Q000235:genetics*; D006801:Humans; D009154:Mutation; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009474:Neurons / Q000166:cytology; D012964:Sodium / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000235:genetics*; D014982:Xenopus laevis
chemical_list: D062552:NAV1.3 Voltage-Gated Sodium Channel; D012964:Sodium; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; Hyperexcitability; Nav channel; Oocyte; Superoxide dismutase