title: Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons.
abstract: Axonal degeneration is a primary cause of permanent neurological disability in individuals with the CNS demyelinating disease multiple sclerosis. Dysfunction of axonal mitochondria and imbalanced energy demand and supply are implicated in degeneration of chronically demyelinated axons. The purpose of this study was to define the roles of mitochondrial volume and distribution in axonal degeneration following acute CNS demyelination. We show that the axonal mitochondrial volume increase following acute demyelination of WT CNS axons does not occur in demyelinated axons deficient in syntaphilin, an axonal molecule that immobilizes stationary mitochondria to microtubules. These findings were supported by time-lapse imaging of WT and syntaphilin-deficient axons in vitro. When demyelinated, axons deficient in syntaphilin degenerate at a significantly greater rate than WT axons, and this degeneration can be rescued by reducing axonal electrical activity with the Na(+) channel blocker flecainide. These results support the concept that syntaphilin-mediated immobilization of mitochondria to microtubules is required for the volume increase of axonal mitochondria following acute demyelination and protects against axonal degeneration in the CNS.
authors: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and.
authors: Nobuhiko
authors: N
authors: Ohno
authors: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and.
authors: Hao
authors: H
authors: Chiang
authors: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and.
authors: Don J
authors: DJ
authors: Mahad
authors: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and.
authors: Grahame J
authors: GJ
authors: Kidd
authors: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and.
authors: LiPing
authors: L
authors: Liu
authors: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and.
authors: Richard M
authors: RM
authors: Ransohoff
authors: Synaptic Function Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
authors: Zu-Hang
authors: ZH
authors: Sheng
authors: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and.
authors: Hitoshi
authors: H
authors: Komuro
authors: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; and trappb@ccf.org.
authors: Bruce D
authors: BD
authors: Trapp
mesh_terms: D001369:Axons; D005260:Female; D006801:Humans; D008565:Membrane Proteins; D008928:Mitochondria / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D059008:Time-Lapse Imaging; D033921:Vesicular Transport Proteins / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C405513:SNPH protein, human; D033921:Vesicular Transport Proteins