Lysosomal glycosphingolipid catabolism by acid ceramidase: formation of glycosphingoid bases during deficiency of glycosidases

Abstract

Glycosphingoid bases are elevated in inherited lysosomal storage disorders with deficient activity of glycosphingolipid catabolizing glycosidases. We investigated the molecular basis of the formation of glucosylsphingosine and globotriaosylsphingosine during deficiency of glucocerebrosidase (Gaucher disease) and α‐galactosidase A (Fabry disease). Independent genetic and pharmacological evidence is presented pointing to an active role of acid ceramidase in both processes through deacylation of lysosomal glycosphingolipids. The potential pathophysiological relevance of elevated glycosphingoid bases generated through this alternative metabolism in patients suffering from lysosomal glycosidase defects is discussed.

Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types

“…In particular, Itier and colleagues have shown that GCS inhibitors can reduce accumulated Gb3, suggesting a role for clearance mechanisms other than α-GalA (45). Alternative molecular clearance mechanisms, which may come into play in situations of high local intracellular Gb3 levels, include removal of the α-galactose by α-N-acetylgalactosaminidase (46,47) or conversion of Gb3 to lysoGb3 by acid ceramidase (6). Overall, the GlcCer, Gb3 and LysoTracker curves overlapped for lucerastat, indicating that the reduction in acidic compartment volume is most likely a consequence of a reduction of glycosphingolipid levels resulting from GCS inhibition.…”

“…The reduced α-GalA activity leads to accumulation of its substrates, globotriaosylceramide (Gb3) and other α-galactose linked neutral glycosphingolipids in many cell types, including podocytes and capillary endothelial cells (5). The accumulated lysosomal Gb3 can be converted to globotriaosylsphingosine (lysoGb3) (6), the plasma levels of which are a useful diagnostic marker, which also show some relationship to genotype and phenotype (7,8). Fabry patients suffer from a range of non-specific, severe symptoms, including neuropathic pain, progressive renal disease, cardiomyopathy, stroke and gastrointestinal problems (1,3,9).…”

Nicotiana benthamiana α-galactosidase A1.1 can functionally complement human α-galactosidase A deficiency associated with Fabry disease

“…Despite the lack of residual α-Gal A, even in classic male FD patients Gb3 accumulation is levelling with age. In Fabry patients accumulating Gb3 is alternatively metabolized in lysosomes by acid ceramidase to globotriaosylsphingosine (lysoGb3) (26). In plasma of male FD patients and mice, lysoGb3 is several hundred-fold elevated, an abnormality that can be exploited for diagnosis and monitoring of disease progression and therapeutic correction (27)(28)(29)(30).…”

Human Alpha Galactosidases Transiently Produced in Nicotiana benthamiana Leaves: New Insights in Substrate Specificities with Relevance for Fabry Disease

“…A recent important insight on pathogenesis of FD stems from the notion that the storage lipid Gb3 is partly actively converted to its sphingoid base globotriaosylsphingosine (Lyso-Gb3) in lysosomes (Aerts et al, 2008; Ferraz et al, 2016a). In symptomatic FD male plasma Lyso-Gb3 is chronically several 100-fold increased, and symptomatic female FD patients also show increased levels of the sphingoid base (Gold et al, 2013; Ferraz et al, 2016a).…”

“…In symptomatic FD male plasma Lyso-Gb3 is chronically several 100-fold increased, and symptomatic female FD patients also show increased levels of the sphingoid base (Gold et al, 2013; Ferraz et al, 2016a). Excessive circulating Lyso-Gb3 seems a culprit, contributing to renal complications and neuropathic pain in FD patients as the results of toxicity for podocytes and nociceptive neurons respectively (Choi et al, 2015; Sanchez-Niño et al, 2015).…”