Abstract
Sphingolipid metabolism starts with the biosynthesis of ceramide, a bioactive lipid and the backbone for the biosynthesis of complex sphingolipids such as sphingomyelin and glycosphingolipids. These are degraded back to ceramide and then to sphingosine, which enters the ceramide–sphingosine-1-phosphate signaling pathway or is further degraded. Several enzymes with multiple catalytic properties and subcellular localizations are thus involved in such metabolism. Hereditary defects of lysosomal hydrolases have been known for several years to be the cause of lysosomal storage diseases such as gangliosidoses, Gaucher disease, Niemann–Pick disease, Krabbe disease, Fabry disease, and Farber disease. More recently, many other inborn errors of sphingolipid metabolism have been recognized, involving enzymes responsible for the biosynthesis of ceramide, sphingomyelin, and glycosphingolipids. Concurrently, epidemiologic and biochemical evidence has established a link between Gaucher disease and Parkinson’s disease, showing that glucocerebrosidase variants predispose individuals to α-synuclein accumulation and neurodegeneration even in the heterozygous status. This appears to be due not only to lysosomal overload of non-degraded glucosylceramide, but to the derangement of vesicle traffic and autophagy, including mitochondrial autophagy, triggered by both sphingolipid intermediates and misfolded proteins. In this review, old and novel disorders of sphingolipid metabolism, in particular those of ganglioside biosynthesis, are evaluated in light of recent investigations of the link between Gaucher disease and Parkinson’s disease, with the aim of better understanding their pathogenic mechanisms and addressing new potential therapeutic strategies.
Highlights
Sphingolipid metabolism starts in the endoplasmic reticulum (ER) with the condensation of serine and palmitic acid, producing 3-keto-dihydrosphingosine, and it continues through successive enzymatic reactions leading to the synthesis of ceramide [1] (Figure 1)
Recent studies on the Gaucher disease (GD)/Parkinson’s disease (PD) relationship demonstrate that GBA variants predispose individuals to PD through molecular mechanisms that have the potential to operate in other disorders affecting sphingolipid metabolism, leading in turn to neurodegeneration
One such mechanism depends on the amounts of individual molecules accumulated. It has been well proven in the case of the inflammatory role played by GlcCer through the activation of complement in the tissues affected by type 1 GD [45]
Summary
Sphingolipid metabolism starts in the endoplasmic reticulum (ER) with the condensation of serine and palmitic acid, producing 3-keto-dihydrosphingosine ( named 3-keto-sphinganine), and it continues through successive enzymatic reactions leading to the synthesis of ceramide [1] (Figure 1). Defects of several enzymes responsible for the biosynthetic steps (Tables 2 and 3) were found to be associated with human diseases: these include variants of serine palmitoyl transferases (SPTLC) [9,10], 3-keto-dihydro-sphingosine reductase (KDSR) [11,12,13], dihydro-ceramide synthases (CERS) [14,15,16,17,18], dihydroceramide desaturase (DEGS) [19,20,21], sphingomyelin synthases (SGMS) [22,23], GlcCer synthase (UGCG) [24], GM3 synthase (ST3GAL5), GM2/GD2/GA2 synthase (B4GALNT1), and CMP-Sial: GlcNAcβ1,3(4) sialyltransferase (ST3GAL3) [25] The latter four enzymes are glycosyltransferases and, the related diseases belong to the wide family of the congenital disorders of glycosylation (CDG) [26]. Emerging data show that heterozygous carriers of glucocerebrosidase GBA [33], sphingomyelinase SMPD1 [36], galactocerebrosidase (GALC) [37], and α-galactosidase (GLA) [38] variants are as much at risk for neurodegenerative diseases such as synucleopathies and multiple sclerosis as those with recessive homozygotes
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