Characterization of small fiber pathology in a mouse model of Fabry disease

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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 I_h and Na_v1.7 currents. We show that in vitro α-GAL silencing increases intracellular Gb3 accumulation paralleled by loss of Na_v1.7 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.

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

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Lukas Hofmann

Department of Neurology, University of Würzburg, Würzburg, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8397-1819
Dorothea Hose

Department of Neurology, University of Würzburg, Würzburg, Germany

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The authors declare that no competing interests exist.
Anne Grießhammer

Department of Neurology, University of Würzburg, Würzburg, Germany

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The authors declare that no competing interests exist.
Robert Blum

Institute of Clinical Neurobiology, University of Würzburg, Würzburg, Germany

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The authors declare that no competing interests exist.
Frank Döring

Institute of Physiology, University of Würzburg, Würzburg, Germany

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The authors declare that no competing interests exist.
Sulayman Dib-Hajj

Center for Neuroscience and Regeneration Research, Yale School of Medicine, West Haven, United States

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4137-1655
Stephen Waxman

Center for Neuroscience and Regeneration Research, Yale School of Medicine, West Haven, United States

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The authors declare that no competing interests exist.
Claudia Sommer

Department of Neurology, University of Würzburg, Würzburg, Germany

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The authors declare that no competing interests exist.
Erhard Wischmeyer

Institute of Physiology, University of Würzburg, Würzburg, Germany

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The authors declare that no competing interests exist.
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.

"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).

Copyright

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.