1. Neuroscience
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Characterization of small fiber pathology in a mouse model of Fabry disease

  1. Lukas Hofmann
  2. Dorothea Hose
  3. Anne Grießhammer
  4. Robert Blum
  5. Frank Döring
  6. Sulayman Dib-Hajj
  7. Stephen Waxman
  8. Claudia Sommer
  9. Erhard Wischmeyer
  10. Nurcan Üçeyler  Is a corresponding author
  1. University of Würzburg, Germany
  2. Yale School of Medicine, United States
Research Article
  • Cited 23
  • Views 2,365
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Cite this article as: eLife 2018;7:e39300 doi: 10.7554/eLife.39300

Abstract

Fabry disease (FD) is a life-threatening X-linked lysosomal storage disorder caused by α-galactosidase A (α-GAL) deficiency. Small fiber pathology and pain are major FD symptoms of unknown pathophysiology. α-GAL deficient mice (GLA KO) age-dependently accumulate globotriaosylceramide (Gb3) in dorsal root ganglion (DRG) neurons paralleled by endoplasmic stress and apoptosis as contributors to skin denervation. Old GLA KO mice show increased TRPV1 protein in DRG neurons and heat hypersensitivity upon i.pl. capsaicin. In turn, GLA KO mice are protected from heat and mechanical hypersensitivity in neuropathic and inflammatory pain models based on reduced neuronal Ih and Nav1.7 currents. We show that in vitro α-GAL silencing increases intracellular Gb3 accumulation paralleled by loss of Nav1.7 currents, which is reversed by incubation with agalsidase-α and lucerastat. We provide first evidence of a direct Gb3 effect on neuronal integrity and ion channel function as potential mechanism underlying pain and small fiber pathology in FD.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Lukas Hofmann

    Department of Neurology, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8397-1819
  2. Dorothea Hose

    Department of Neurology, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Anne Grießhammer

    Department of Neurology, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Robert Blum

    Institute of Clinical Neurobiology, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Frank Döring

    Institute of Physiology, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Sulayman Dib-Hajj

    Center for Neuroscience and Regeneration Research, Yale School of Medicine, West Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4137-1655
  7. Stephen Waxman

    Center for Neuroscience and Regeneration Research, Yale School of Medicine, West Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Claudia Sommer

    Department of Neurology, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Erhard Wischmeyer

    Institute of Physiology, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Nurcan Üçeyler

    Department of Neurology, University of Würzburg, Würzburg, Germany
    For correspondence
    ueceyler_n@ukw.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6973-6428

Funding

Interdisciplinary Center for Clinical Research Würzburg (N260)

  • Lukas Hofmann

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Our study was approved by the Bavarian State authorities (Regierung von Unterfranken, # 54/12).

Reviewing Editor

  1. Allan Basbaum, University of California, San Francisco, United States

Publication history

  1. Received: June 18, 2018
  2. Accepted: October 11, 2018
  3. Accepted Manuscript published: October 17, 2018 (version 1)
  4. Version of Record published: November 26, 2018 (version 2)

Copyright

© 2018, Hofmann et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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