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.
Highlights
Thermal hyposensitivity and pain based on small nerve fiber pathology are cardinal neurological symptoms of the progressive and life-threatening X-linked Fabry disease (FD) (Zarate and Hopkin, 2008)
Age-dependent Gb3 accumulation in dorsal root ganglion (DRG) neurons of galactosidase A knockout mouse (GLA KO) mice is associated with increased endoplasmic stress and skin denervation
We asked if Gb3 deposits are present and where they are located in DRG neurons of young and old GLA KO mice
Summary
Thermal hyposensitivity and pain based on small nerve fiber pathology are cardinal neurological symptoms of the progressive and life-threatening X-linked Fabry disease (FD) (Zarate and Hopkin, 2008). While genetically caused reduction or loss of a-galactosidase A (a-GAL) with consecutive lysosomal accumulation of globotriaosylceramide (Gb3) has long been considered the pathophysiological key event in FD (Romeo and Migeon, 1970), the mechanisms underlying sensory impairment, pain, and denervation remain unclear. The finding of potential Gb3 deposits in dorsal root ganglion (DRG) neurons (Gadoth and Sandbank, 1983; Lakomaet al., 2016; Marshall et al, 2010) and the presence of peripheral neuropathy mostly of the small fiber type (Uc ̧ eyler et al, 2011) supports the hypothesis of a pathophysiological mechanism involving Gb3 accumulation. Having investigated the largest and oldest cohort (>24 months) reported far for the a-GAL deficient (GLA KO) mouse model of FD, we previously described an age-dependent development of thermal hyposensitivity mirroring the clinical phenotype (Uc ̧ eyler et al, 2016).
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