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

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.

Role of Gangliosides in Peripheral Pain Mechanisms

“…Prominent morphological changes of the affected thin myelinated and unmyelinated sensory axons are the reduction of the intraepidermal fiber density in the skin [31][32][33] and reduction in the density and length of corneal nerve fibers [32,34]. Swelling of the dorsal root ganglion neurons and accumulation of Gb3 in the cytoplasm of these cells were also reported in human autopsy samples [35,36] and in α-galactosidase knock out animals [28,29]. In human sural nerve biopsy material ultrastructural morphometric analysis showed a reduction of the number of both small diameter myelinated axons and unmyelinated axons [36] and appearance of regenerating clusters was also reported [36,37].…”

“…Symptoms of autonomic neuropathy such as reduced sweating and hypohydrosis, reduced heart rate variability, orthostatic hypotonia and gastrointestinal dysmobility are also frequent complications of the disease [26]. In different animal models, similar abnormalities of sensory and autonomic functions have been observed after genetic deletion of the α-galactosidase gene [28][29][30]. Prominent morphological changes of the affected thin myelinated and unmyelinated sensory axons are the reduction of the intraepidermal fiber density in the skin [31][32][33] and reduction in the density and length of corneal nerve fibers [32,34].…”

Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease

“…Several α-GLA animal models have been generated to better understand Fabry disease pathogenesis [60][61][62][63]. Among them, one Gla knock-out model, also overexpressing the Gb3 synthase, developed a significant neurological phenotype characterized by spontaneous tremors, slowed movements and gait disturbances [64].…”

Ion channels and neuropathic pain

“…Now, in eLife, Nurcan Üçeyler of the University of Würzburg and co-workers at Würzburg and Yale Medical School and Veterans Affairs Hospital – including Lukas Hofmann as first author – fill in some of the blanks ( Hofmann et al, 2018 ). The team elegantly combined molecular, histological, electrophysiological and behavioral techniques to study a mouse model of Fabry disease in which the gene for α-GAL has been deactivated (or ‘knocked out’).…”

“…The team elegantly combined molecular, histological, electrophysiological and behavioral techniques to study a mouse model of Fabry disease in which the gene for α-GAL has been deactivated (or ‘knocked out’). It was already known that as these mice get older, Gb3 accumulates within and around the cell bodies of their small fiber neurons in the sensory ganglia ( Gadoth and Sandbank, 1983 ; Hofmann et al, 2018 ). Located near the spinal cord, these ganglia help the body process sensations.…”