Assessing the role of glycosphingolipids in the phenotype severity of Fabry disease mouse model

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 (Gb 3 ), globotriaosylsphingosine (lyso-Gb 3 ), and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb 3 isoforms (various fatty acids) and lyso-Gb 3 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 Gb 3 and lyso-Gb 3 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 Gb 3 and particular lyso-Gb 3 analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared with Fabry-B6. By contrast, there was no difference in Gb 3 and lyso-Gb 3 isoforms/analogs in the kidneys and DRG between the two strains. Furthermore, using immunohistochemistry, we found that Gb 3 massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb 3 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 Gb 3 or lyso-Gb 3 may play major roles in the pathogenesis of Fabry disease, and that Gb 3 and lyso-Gb 3 are not responsible for the pathology in all tissues or cell types.