The Glycosphingolipid Metabolic Pathway in Lysosomal Storage Diseases

What are GSLs?

Glycosphingolipids (GSLs) are lipids comprised of a hydrophilic sugar chain attached to a hydrophobic membrane lipid anchor, ceramide.1,2 GSLs are important building blocks of cell membranes and fulfill diverse functions.2,3 They are vital to maintaining cellular homeostasis and contribute to physiological processes such as cell signaling and regulation of inflammation.2-5

GSL functions provide2,3,5:

Cell membrane building blocks
Cell membrane
building blocks
Cellular homeostasis
Cellular homeostasis
Myelin insulation of axons
Myelin insulation
of axons
Regulation of T cells
of T cells
Cell signaling
Expression of blood group antigens
Expression of blood
group antigens

The GSL metabolic pathway

GSL formation occurs in the Golgi apparatus of cells, and degradation happens in lysosomes. One of the first steps in GSL formation is catalyzed by an enzyme called glucosylceramide synthase (GCS) at the top of the GSL pathway.4,6,7 Tight regulation of the biosynthesis, degradation, and intracellular tracking of GSLs is necessary as they serve many critical functions for cells.3

GSL metabolic pathway and lysosomal storage diseases

Pathogenic variants compromise the lysosomal enzymes responsible for degrading GSLs, which can lead to lysosomal storage diseases (LSDs). The progressive and relentless pathologic accumulation of substrates such as GSLs in lysosomes, which can eventually affect cell functions, is the hallmark of LSDs.2,8 The affected cells become functionally impaired or destroyed, leading to toxic effects in the different LSDs.9

Cell membrane Normal Lysosome Lysosomal storage diseases
storage diseases
Adapted from Mashima R et al. Int J Mol Sci. 2020;21(8):E2704.

The GSL Metabolic Pathway4,5,9,11-14


Lysosomal storage diseases
storage diseases
GSL accumulation
GSL accumulation
Enzyme deficiency
Enzyme deficiency
GSL metabolic pathway GSL metabolic pathway
Sphingomyelin synthase
Acid sphingomyelinase
Acid β-glucosidase (GBA)
Glucosylceramide synthase (GCS)
GSL: glucosylceramide (GL-1)
GL-3 synthase
Ganglioside GM3
GM2 synthase
GSL: globotriaosylceramide (GL-3)
GSL: ganglioside GM2

For illustrative purposes only.

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