title: Activity of NaV1.2 promotes neurodegeneration in an animal model of multiple sclerosis.
abstract: Counteracting the progressive neurological disability caused by neuronal and axonal loss is the major unmet clinical need in multiple sclerosis therapy. However, the mechanisms underlying irreversible neuroaxonal degeneration in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) are not well understood. A long-standing hypothesis holds that the distribution of voltage-gated sodium channels along demyelinated axons contributes to neurodegeneration by increasing neuroaxonal sodium influx and energy demand during CNS inflammation. Here, we tested this hypothesis in vivo by inserting a human gain-of-function mutation in the mouse NaV1.2-encoding geneScn2athat is known to increase NaV1.2-mediated persistent sodium currents. In mutant mice, CNS inflammation during EAE leads to elevated neuroaxonal degeneration and increased disability and lethality compared with wild-type littermate controls. Importantly, immune cell infiltrates were not different between mutant EAE mice and wild-type EAE mice. Thus, this study shows that increased neuronal NaV1.2 activity exacerbates inflammation-induced neurodegeneration irrespective of immune cell alterations and identifies NaV1.2 as a promising neuroprotective drug target in multiple sclerosis.
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schattling
authors.affiliation: Institut für Molekulare und Verhaltensneurowissenschaften, Universität zu Köln, Köln, Germany.|Deutsches Zentrum für Neurodegenerative Erkrankungen, Bonn, Germany.|Klinik für Kinder- und Jugendmedizin, Uniklinik Köln, Köln, Germany.
authors.forename: Walid
authors.initials: W
authors.lastname: Fazeli
authors.affiliation: Institut für Molekulare und Verhaltensneurowissenschaften, Universität zu Köln, Köln, Germany.|Deutsches Zentrum für Neurodegenerative Erkrankungen, Bonn, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Engeland
authors.affiliation: Abteilung Neurologie mit Schwerpunkt Epileptologie, Hertie-Institut für klinische Hirnforschung, Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Abteilung Neurologie mit Schwerpunkt Epileptologie, Hertie-Institut für klinische Hirnforschung, Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.affiliation: Institut für Molekulare und Verhaltensneurowissenschaften, Universität zu Köln, Köln, Germany.|Deutsches Zentrum für Neurodegenerative Erkrankungen, Bonn, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Isbrandt
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Friese
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000473:pathology*; D000073659:Gain of Function Mutation; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics*; D009410:Nerve Degeneration / Q000473:pathology*
chemical_list: D062551:NAV1.2 Voltage-Gated Sodium Channel