Abstract
Fabry disease is caused by deficient activity of α-galactosidase A, an enzyme that hydrolyzes the terminal α-galactosyl moieties from glycolipids and glycoproteins, and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb3 isoforms (various fatty acids) and lyso-Gb3 analogs (various sphingosine modifications) in two strains of Fabry disease mouse models: a pure C57BL/6 (B6) background or a B6/129 mixed background, with the latter exhibiting more prominent cardiac and renal hypertrophy and thermosensation deficits. Total Gb3 and lyso-Gb3 levels in the heart, kidney, and dorsal root ganglion (DRG) were similar in the two strains. However, levels of the C20-fatty acid isoform of Gb3 and particular lyso-Gb3 analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared with Fabry-B6. By contrast, there was no difference in Gb3 and lyso-Gb3 isoforms/analogs in the kidneys and DRG between the two strains. Furthermore, using immunohistochemistry, we found that Gb3 massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb3 accumulation was not observed in nonpeptidergic nociceptors, the disease-relevant subpopulation that has remarkably increased isolectin-B4 (the marker of nonpeptidergic nociceptors) binding and enlarged cell size. These findings suggest that specific species of Gb3 or lyso-Gb3 may play major roles in the pathogenesis of Fabry disease, and that Gb3 and lyso-Gb3 are not responsible for the pathology in all tissues or cell types.
Highlights
Fabry disease is an X-linked metabolic disorder that results from deficiency of the lysosomal hydrolase, galactosidase A ( -gal A) [1], which leads to intracellular
Given that Gb3 biosynthesis is precisely controlled in a cell type-specific manner and is regulated by various factors including cell cycle and cytokines [16, 17], it can be expected that the constitutive overexpression of A4GALT under ubiquitous CAG promoter would produce a different cellular distribution of Gb3 compared with the intrinsic distribution pattern in Fabry disease
Cardiac and renal hypertrophy appeared at age 6 months in Fabry-B6/129 but at age 12 months in Fabry-B6 (Fig. 1A, D)
Summary
Fabry disease is an X-linked metabolic disorder that results from deficiency of the lysosomal hydrolase, galactosidase A ( -gal A) [1], which leads to intracellular. Given that Gb3 biosynthesis is precisely controlled in a cell type-specific manner (as suggested in the present study) and is regulated by various factors including cell cycle and cytokines [16, 17], it can be expected that the constitutive overexpression of A4GALT under ubiquitous CAG promoter would produce a different cellular distribution of Gb3 compared with the intrinsic distribution pattern in Fabry disease. These A4GALT-transgenic Fabry mice exhibit neurological symptoms (e.g., spontaneous tremor) that do not develop in Fabry disease [15]. To evaluate the potential involvement of Gb3 in small-fiber neuropathy, we investigated patterns of Gb3 distribution in sensory neuron subpopulations of dorsal root ganglion (DRG) in Fabry mice
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call