Characterization of small fiber pathology in a mouse model of Fabry disease
- University of Würzburg, Germany
- Yale School of Medicine, United States
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.
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Author details
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
© 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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Characterization of small fiber pathology in a mouse model of Fabry disease
eLife 7:e39300.
https://doi.org/10.7554/eLife.39300
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