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:
building blocks
of axons
of T cells
signaling
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
Lysosome10
Normal
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
Legend:
storage diseases
Sphingomyelin
Sphingomyelin synthase
Acid sphingomyelinase
Ceramide
Acid β-glucosidase (GBA)
Glucosylceramide synthase (GCS)
GSL: glucosylceramide (GL-1)
Lactosylceramide
GL-3 synthase
Ganglioside GM3
α-galactosidase
A
A
β-hexosaminidase
GM2 synthase
GSL: globotriaosylceramide (GL-3)
GSL: ganglioside GM2
For illustrative purposes only.
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Glycosphingolipid metabolism and polycystic kidney disease. Cell Signal. 2020;69:109526. doi:10.1016/j.cellsig.2020.109526 7. Grassi S, Chiricozzi E, Mauri L, Sonnino S, Prinetti A. Sphingolipids and neuronal degeneration in lysosomal storage disorders. J Neurochem. 2019;148(5):600-611. doi:10.1111/jnc.14540 8. Dodge JC. Lipid involvement in neurodegenerative diseases of the motor system: insights from lysosomal storage diseases. Front Mol Neurosci. 2017;10:356. doi:10.3389/fnmol.2017.00356 9. Schulze H, Sandhoff K. Lysosomal lipid storage diseases. Cold Spring Harb Perspect Biol. 2011;3(6):a004804. doi:10.1101/cshperspect.a004804 10. Mashima R, Okuyama T, Ohira M. Biomarkers for lysosomal storage disorders with an emphasis on mass spectrometry. Int J Mol Sci. 2020;21(8):E2704. doi:10.3390/ijms21082704 11. McGovern MM, Lippa N, Bagiella E, Schuchman EH, Desnick RJ, Wasserstein MP. Morbidity and mortality in type B Niemann-Pick disease. 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