Abstract
Glycosphingolipids (GSLs) are a specialized class of membrane lipids composed of a ceramide backbone and a carbohydrate-rich head group. GSLs populate lipid rafts of the cell membrane of eukaryotic cells, and serve important cellular functions including control of cell–cell signaling, signal transduction and cell recognition. Of the hundreds of unique GSL structures, anionic gangliosides are the most heavily implicated in the pathogenesis of lysosomal storage diseases (LSDs) such as Tay-Sachs and Sandhoff disease. Each LSD is characterized by the accumulation of GSLs in the lysosomes of neurons, which negatively interact with other intracellular molecules to culminate in cell death. In this review, we summarize the biosynthesis and degradation pathways of GSLs, discuss how aberrant GSL metabolism contributes to key features of LSD pathophysiology, draw parallels between LSDs and neurodegenerative proteinopathies such as Alzheimer’s and Parkinson’s disease and lastly, discuss possible therapies for patients.
Highlights
Glycolipids consist of at least one sugar residue covalently linked to a lipid moiety and can be categorized into two groups: (1) glyceroglycolipids, which are composed of a glycerol backbone, at least one fatty acid and a carbohydrate, and (2) glycosphingolipids (GSLs), composed of an N-acylated, unsaturated amino alcohol sphingosine and at least one carbohydrate residue
In a patient with West syndrome (ST3Gal III-congenital disorders of glycosylation (CDG)), an illness characterized by epileptic spasms, abnormal brain waves and intellectual disability [75], the α2,3-sialyltransferase III was found to be deficient, decreasing α2-3sialylation of Gal linked to GalNAc in GD1a, GT1b and GQ1c, which causes an accumulation of GM1
Considering the significant reduction in cellular waste disposal in lysosomal storage diseases (LSDs), we propose the overwhelming lipid load may cause disruption of the lysosomal membrane rendering it unable to fuse with autophagosomes, which may indirectly lead to cell death
Summary
Glycolipids consist of at least one sugar residue covalently linked to a lipid moiety and can be categorized into two groups: (1) glyceroglycolipids, which are composed of a glycerol backbone, at least one fatty acid and a carbohydrate, and (2) glycosphingolipids (GSLs), composed of an N-acylated, unsaturated amino alcohol sphingosine (ceramide) and at least one carbohydrate residue. GSLs are amphipathic due to the presence of a variable hydrophilic carbohydrate-rich head group and a hydrophobic ceramide tail. Glucuronoglycosphingolipids, sulfatoglycosphingolipids, phospho- and phosphono-glycosphingolipids and gangliosides constitute the anionic group of GSLs. Glyceroglycolipids are infrequently found in humans, but are ubiquitous throughout plant cells. The hydrophobic ceramide moiety anchors the GSL into the membrane, while the hydrophilic glycan extrudes into the extracellular space and can interact with other membrane-bound and extracellular carbohydrate-binding molecules. Perturbation in GSL homeostasis results in serious pathological consequences and is the cause of various metabolic disorders, which will be discussed later in the current review
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