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

Elife. 2018 Oct 17;7:e39300. doi: 10.7554/eLife.39300.


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 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.

Keywords: Fabry disease; alpha-galactosidase A; globotriaosylceramide; human biology; medicine; mouse; neuroscience; pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Fabry Disease / pathology*
  • Ganglia, Spinal / pathology*
  • Gene Knockdown Techniques
  • Mice
  • Mice, Knockout
  • NAV1.7 Voltage-Gated Sodium Channel / analysis
  • Neurons / pathology*
  • Trihexosylceramides / analysis
  • alpha-Galactosidase / genetics
  • alpha-Galactosidase / metabolism


  • NAV1.7 Voltage-Gated Sodium Channel
  • Scn9a protein, mouse
  • Trihexosylceramides
  • globotriaosylceramide
  • alpha-Galactosidase

Grant support

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