title: Pervasive axonal transport deficits in multiple sclerosis models.
abstract: Impaired axonal transport can contribute to axon degeneration and has been described in many neurodegenerative diseases. Multiple sclerosis (MS) is a common neuroinflammatory disease, which is characterized by progressive axon degeneration-whether, when, and how axonal transport is affected in this condition is unknown. Here we used in vivo two-photon imaging to directly assay transport of organelles and the stability of microtubule tracks in individual spinal axons in mouse models of MS. We found widespread transport deficits, which preceded structural alterations of axons, cargos, or microtubules and could be reversed by acute anti-inflammatory interventions or redox scavenging. Our study shows that acute neuroinflammation induces a pervasive state of reversible axonal dysfunction, which coincides with acute disease symptoms. Moreover, perpetuated transport dysfunction, as we found in a model of progressive MS, led to reduced distal organelle supply and could thus contribute to axonal dystrophy in advanced stages of the disease.
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig-Maximilians Universität München, Marchioninistraße 17, 81377 Munich, Germany; Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors.forename: Catherine Diamante
authors.initials: CD
authors.lastname: Sorbara
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig-Maximilians Universität München, Marchioninistraße 17, 81377 Munich, Germany.
authors.forename: Naomi Elizabeth
authors.initials: NE
authors.lastname: Wagner
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig-Maximilians Universität München, Marchioninistraße 17, 81377 Munich, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Ladwig
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig-Maximilians Universität München, Marchioninistraße 17, 81377 Munich, Germany.
authors.forename: Ivana
authors.initials: I
authors.lastname: Nikić
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Rue Michel Servet 1, 1211 Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; Department of Neuropathology, Georg-August-Universität Göttingen, Robert-Koch-Str. 40, 37099 Göttingen, Germany.
authors.forename: Doron
authors.initials: D
authors.lastname: Merkler
authors.affiliation: Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Kleele
authors.affiliation: Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors.forename: Petar
authors.initials: P
authors.lastname: Marinković
authors.affiliation: Transgenic Core Facility, Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, 01307 Dresden, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Naumann
authors.affiliation: Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors.forename: Leanne
authors.initials: L
authors.lastname: Godinho
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig-Maximilians Universität München, Marchioninistraße 17, 81377 Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Straße 17, 81377 Munich, Germany.
authors.forename: Florence Martine
authors.initials: FM
authors.lastname: Bareyre
authors.affiliation: Department of Physiology, Indiana University School of Medicine-Muncie, Cooper Science Building, CL 215, Muncie, IN 47306, USA.
authors.forename: Derron
authors.initials: D
authors.lastname: Bishop
authors.affiliation: Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Straße 17, 81377 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen Straße 17, 81377 Munich, Germany; Center of Integrated Protein Science (CIPSM), Butenandtstraße 5-13, 81377 Munich, Germany. Electronic address: thomas.misgeld@lrz.tu-muenchen.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Misgeld
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig-Maximilians Universität München, Marchioninistraße 17, 81377 Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Straße 17, 81377 Munich, Germany. Electronic address: martin.kerschensteiner@med.uni-muenchen.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Kerschensteiner
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology*; D001369:Axons / Q000502:physiology*; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology; D059907:Functional Neuroimaging; D051379:Mice; D008870:Microtubules / Q000502:physiology; D009103:Multiple Sclerosis / Q000473:pathology* / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000503:physiopathology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D015388:Organelles / Q000502:physiology; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D013116:Spinal Cord / Q000502:physiology
chemical_list: D016166:Free Radical Scavengers; D020030:Nitric Oxide Donors; C091861:spermine nitric oxide complex; D013096:Spermine