Axonal alterations in demyelinating diseases

Summary

Principal Investigator: STEVEN SIMON SCHERER
Abstract: We hypothesize that in normal myelinated PNS axons, the combination of Kv1.1, Kv1.2, KCNQ2, and KCNQ3 is necessary for repolarization, and that the misexpression of Kv3.1 b has a deleterious effect on axonal conduction of de/remyelinated axons. In unpublished work, we have found the alphas isoform of Na,K-ATPase is the only one that is clearly localized to axons, that it is (surprisingly) excluded from nodes, and appears to be focally diminished by demyelination. Thus, we also hypothesize that the misexpression of alphas may contribute to depolarization of de/remyelinated axons. The proposed experiments build on these findings, with the central theme of illuminating how K+ homeostasis works in normal and de/remyelinated axons. Aim #1: Do Kv3.1b channels contribute to conduction failure in demyelinating diseases? We will investigate whether KvS.lb is the 4-AP-sensitive channel by comparing the effects of DTX-I and 4- AP on axonal conduction in TremblerJ mice on a KvS.lb -null (Kcncl-/-) versus Kcnc1+/+ background. Aim #2: What is the role of KCNQ2 in myelinated axons? Because Kcnq2-null mice die at birth, before myelination and the formation of nodes, we will generate a conditional Kcnq2-null mouse and analyze the structure and function of myelinated axons, including the expression of KCNQ3. Aim #3: What Na,K-ATPase isoforms are expressed by myelinated axons and demyelinated axons? we will localize alpha1-3 by immunoelectron microscopy in CMSand PNS myelinated axons, along with their beta subunits.
Funding Period: ----------------2002 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon
    Zongming Pan
    Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 26:2599-613. 2006
  2. ncbi Kv7.2 regulates the function of peripheral sensory neurons
    Chih H King
    Department of Neuroscience, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104
    J Comp Neurol 522:3262-80. 2014
  3. pmc Tight junctions potentiate the insulative properties of small CNS myelinated axons
    Jerome Devaux
    Département Signalisation Neuronale, Le Centre de Recherche de Neurobiologie Neurophysiologie de Marseille, UMR 6231, CNRS, Universite de la Mediterranee, Universite Paul Cezanne, Institut Federatif de Recherche Jean Roche, Marseille, France
    J Cell Biol 183:909-21. 2008
  4. pmc Molecular mechanisms of inherited demyelinating neuropathies
    Steven S Scherer
    The University of Pennsylvania Medical School, Philadelphia, Pennsylvania
    Glia 56:1578-89. 2008
  5. pmc National Institute of Neurological Disorders and Stroke (NINDS): advances in understanding and treating neuropathy, 24-25 October 2006; Bethesda, Maryland
    Eva L Feldman
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 2200, USA
    J Peripher Nerv Syst 13:1-6. 2008
  6. pmc Cell expression of GDAP1 in the nervous system and pathogenesis of Charcot-Marie-Tooth type 4A disease
    Laia Pedrola
    Department of Genomics and Proteomics, Instituto de Biomedicina, CSIC, Valencia, Spain
    J Cell Mol Med 12:679-89. 2008
  7. ncbi Neuromyotonia and limbic encephalitis sera target mature Shaker-type K+ channels: subunit specificity correlates with clinical manifestations
    Kleopas A Kleopa
    Department of Clinical Neurosciences, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus, PA, USA
    Brain 129:1570-84. 2006
  8. ncbi Kv7.5 is the primary Kv7 subunit expressed in C-fibers
    Chih H King
    Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Comp Neurol 520:1940-50. 2012
  9. pmc Paranodal permeability in "myelin mutants"
    Seema Shroff
    Department Physiology and Neuroscience, NYU School of Medicine, New York, New York, USA
    Glia 59:1447-57. 2011
  10. pmc Central nervous system dysfunction in a mouse model of FA2H deficiency
    Kathleen A Potter
    Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    Glia 59:1009-21. 2011

Scientific Experts

  • Sabrina W Yum
  • Eric Lancaster
  • Chih H King
  • Steven S Scherer
  • Kleopas A Kleopa
  • Seema Shroff
  • Kathleen A Potter
  • Natalie Vavlitou
  • Laia Pedrola
  • Eva L Feldman
  • Jerome Devaux
  • Zongming Pan
  • Jian J Li
  • P Akbar Ali Khan
  • Hua Cheng
  • Jagadish Kummetha Venkata
  • Jack Rosenbluth
  • Amanda Mierzwa
  • Xianlin Han
  • Moses V Chao
  • Juan C Arévalo
  • George Fullbright
  • Michael J Kern
  • Hiroko Hama
  • Elior Peles
  • Jacek Bielawski
  • Barbel Rohrer
  • Kyriaki Markoullis
  • Irene Sargiannidou
  • Kyriacos Kyriacou
  • Francesc Palau
  • Maribel Sanchez-Piris
  • Lawrence Wrabetz
  • Antonio Espert
  • Erich E Sirkowski
  • David R Cornblath
  • Isabel Farinas
  • Teresa Valdés-Sánchez
  • John Porter
  • Alexander Gow
  • Steven Scherer
  • Robert Dworkin
  • Jai Yoon Sul
  • Edward C Cooper
  • Julia Lemos
  • Bethan Lang
  • Tingching Kao
  • Angela Vincent
  • Stephen D Cranstoun
  • Zsolt Horvath
  • Vann Bennett
  • Lauren B Elman

Detail Information

Publications14

  1. ncbi A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon
    Zongming Pan
    Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 26:2599-613. 2006
    ..This includes the historical period when myelin also evolved...
  2. ncbi Kv7.2 regulates the function of peripheral sensory neurons
    Chih H King
    Department of Neuroscience, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104
    J Comp Neurol 522:3262-80. 2014
    ..Taken together, our results suggest that the loss of Kv7.2 activity increases the excitability of primary sensory neurons...
  3. pmc Tight junctions potentiate the insulative properties of small CNS myelinated axons
    Jerome Devaux
    Département Signalisation Neuronale, Le Centre de Recherche de Neurobiologie Neurophysiologie de Marseille, UMR 6231, CNRS, Universite de la Mediterranee, Universite Paul Cezanne, Institut Federatif de Recherche Jean Roche, Marseille, France
    J Cell Biol 183:909-21. 2008
    ..Together, our data shed new light on myelin structural components and our understanding of the biology and pathophysiology of this membrane...
  4. pmc Molecular mechanisms of inherited demyelinating neuropathies
    Steven S Scherer
    The University of Pennsylvania Medical School, Philadelphia, Pennsylvania
    Glia 56:1578-89. 2008
    ..Here, we review selected recent developments from work on the molecular mechanisms of these disorders and their implications for treatment strategies...
  5. pmc National Institute of Neurological Disorders and Stroke (NINDS): advances in understanding and treating neuropathy, 24-25 October 2006; Bethesda, Maryland
    Eva L Feldman
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 2200, USA
    J Peripher Nerv Syst 13:1-6. 2008
    ..Short-term goals of the workshop were to form a working group for neuropathy, the Peripheral Neuropathy Study Group, and to translate new scientific findings into therapies and complete clinical trials...
  6. pmc Cell expression of GDAP1 in the nervous system and pathogenesis of Charcot-Marie-Tooth type 4A disease
    Laia Pedrola
    Department of Genomics and Proteomics, Instituto de Biomedicina, CSIC, Valencia, Spain
    J Cell Mol Med 12:679-89. 2008
    ....
  7. ncbi Neuromyotonia and limbic encephalitis sera target mature Shaker-type K+ channels: subunit specificity correlates with clinical manifestations
    Kleopas A Kleopa
    Department of Clinical Neurosciences, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus, PA, USA
    Brain 129:1570-84. 2006
    ..Although more than one type of antibody is often detectable in individual sera, higher affinity for certain subunits or subunit combinations may determine the range of clinical manifestations...
  8. ncbi Kv7.5 is the primary Kv7 subunit expressed in C-fibers
    Chih H King
    Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Comp Neurol 520:1940-50. 2012
    ..2 or Kv7.3, which are instead localized to nodes of Ranvier and the cell bodies of large sensory neurons. These data suggest that Kv7.5 provides the primary M current in nociceptive neurons...
  9. pmc Paranodal permeability in "myelin mutants"
    Seema Shroff
    Department Physiology and Neuroscience, NYU School of Medicine, New York, New York, USA
    Glia 59:1447-57. 2011
    ....
  10. pmc Central nervous system dysfunction in a mouse model of FA2H deficiency
    Kathleen A Potter
    Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
    Glia 59:1009-21. 2011
    ..These findings provide the first evidence that FA2H has an important function outside of oligodendrocytes in the CNS...
  11. pmc Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia
    Eric Lancaster
    Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA
    Ann Neurol 69:303-11. 2011
    ....
  12. pmc Axonal pathology precedes demyelination in a mouse model of X-linked demyelinating/type I Charcot-Marie Tooth neuropathy
    Natalie Vavlitou
    Neuroscience Laboratory and Neurology Clinics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
    J Neuropathol Exp Neurol 69:945-58. 2010
    ..These findings demonstrate that axonal abnormalities including impaired cytoskeletal organization and defects in axonal transport precede demyelination in this mouse model of CMT1X...
  13. pmc A patient with neurofibromatosis type 1 and Charcot-Marie-Tooth disease type 1B
    Eric Lancaster
    Department of Neurology, University of Pennsylvania Medical Center, 3400 Spruce Street, 3W Gates Neurology, Philadelphia, Pennsylvania 19104, USA
    Muscle Nerve 41:555-8. 2010
    ..Although one might expect an overwhelming tumor burden due to the combination of these two disorders, the two mutations did not appear to interact...
  14. ncbi A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy
    Sabrina W Yum
    Section of Neurology, St Christopher s Hospital For Children, Drexel University College of Medicine, Philadelphia, PA 19134, USA
    Ann Neurol 66:759-70. 2009
    ..To report the first cases of a homozygous recessive mutation in NEFL, the gene that encodes the light subunit of neurofilaments...