Abstract
Glycosphingolipids (GSLs) are a diverse group of membrane components occurring mainly on the surfaces of mammalian cells. They and their metabolites have a role in intercellular communication, serving as versatile biochemical signals (Kaltner et al, Biochem J 476(18):2623–2655, 2019) and in many cellular pathways. Anionic GSLs, the sialic acid containing gangliosides (GGs), are essential constituents of neuronal cell surfaces, whereas anionic sulfatides are key components of myelin and myelin forming oligodendrocytes. The stepwise biosynthetic pathways of GSLs occur at and lead along the membranes of organellar surfaces of the secretory pathway. After formation of the hydrophobic ceramide membrane anchor of GSLs at the ER, membrane-spanning glycosyltransferases (GTs) of the Golgi and Trans-Golgi network generate cell type-specific GSL patterns for cellular surfaces. GSLs of the cellular plasma membrane can reach intra-lysosomal, i.e. luminal, vesicles (ILVs) by endocytic pathways for degradation. Soluble glycoproteins, the glycosidases, lipid binding and transfer proteins and acid ceramidase are needed for the lysosomal catabolism of GSLs at ILV-membrane surfaces. Inherited mutations triggering a functional loss of glycosylated lysosomal hydrolases and lipid binding proteins involved in GSL degradation cause a primary lysosomal accumulation of their non-degradable GSL substrates in lysosomal storage diseases (LSDs). Lipid binding proteins, the SAPs, and the various lipids of the ILV-membranes regulate GSL catabolism, but also primary storage compounds such as sphingomyelin (SM), cholesterol (Chol.), or chondroitin sulfate can effectively inhibit catabolic lysosomal pathways of GSLs. This causes cascades of metabolic errors, accumulating secondary lysosomal GSL- and GG- storage that can trigger a complex pathology (Breiden and Sandhoff, Int J Mol Sci 21(7):2566, 2020).
Dedicated to Professor Kunihiko Suzuki on the occasion of his 90th birthday.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
Abbreviations
- ASA:
-
Arylsulfatase A
- ASM:
-
Acid sphingomyelinase
- BMP:
-
Bis(monoacylglycero)phosphate
- CAD:
-
Cationic amphiphilic drug
- Cer:
-
Ceramide
- CerS:
-
Ceramide synthase
- CERT:
-
Ceramide transfer protein
- Chol:
-
Cholesterol
- CNS:
-
Central nervous system
- ER:
-
Endoplasmic reticulum
- FA:
-
Fatty acid
- GalCer:
-
β-galactosylceramide; Ganglioside names are abbreviated according to Svennerholm (1962, 1994) as recommended by IUPAC (Chester 1997)
- GBA1:
-
lysosomal β-glucocerebrosidase
- GlcCer:
-
β-glucosylceramide
- GM2AP:
-
GM2 activator protein
- GRN:
-
Granulin
- GT:
-
Glycosyltransferase
- Hex A/B/S:
-
β-hexosaminidase A/B/S
- KDS:
-
3-keto-dihydrosphingosine
- KDSR:
-
Keto-dihydrosphingosine reductase
- LacCer:
-
Lactosylceramide
- NEU:
-
Neuraminidase
- NPC:
-
Niemann–Pick disease type C protein
- PA:
-
Phosphatidic acid
- PD:
-
Parkinson disease
- PG:
-
Phosphatidylglycerol
- PI:
-
Phosphatidylinositol
- PiP:
-
Phosphatidyl inositol phosphate
- PL:
-
Phospholipid
- PM:
-
Plasma membrane
- PS:
-
Phosphatidylserine
- Sa:
-
Sphinganine
- Sap:
-
Saposin
- SAP:
-
Sphingolipid activator protein
- SL:
-
Sphingolipid
- SM:
-
Sphingomyelin
- SM4g:
-
Seminolipid, i.e. 3-sulfogalactosyl-1-alkyl-2-acylglycerol
- SM4s:
-
3-sulfogalactosylceramide
- So:
-
Sphingosine
- S1P:
-
Sphingosine 1-phosphate
- SPT:
-
Serine palmitoyltransferase
- TGN:
-
Trans Golgi network
References
Abdelkarim H, Marshall MS, Scesa G, Smith RA, Rue E, Marshall J, et al. alpha-Synuclein interacts directly but reversibly with psychosine: implications for alpha-synucleinopathies. Sci Rep. 2018;8(1):12462.
Abdul-Hammed M, Breiden B, Adebayo MA, Babalola JO, Schwarzmann G, Sandhoff K. Role of endosomal membrane lipids and NPC2 in cholesterol transfer and membrane fusion. J Lipid Res. 2010;51(7):1747–60.
Abdul-Hammed M, Breiden B, Schwarzmann G, Sandhoff K. Lipids regulate the hydrolysis of membrane bound glucosylceramide by lysosomal beta-glucocerebrosidase. J Lipid Res. 2017;58(3):563–77.
Abreu CA, Teixeira-Pinheiro LC, Lani-Louzada R, da Silva-Junior AJ, Vasques JF, Gubert F, et al. GD3 synthase deletion alters retinal structure and impairs visual function in mice. J Neurochem. 2021;158(3):694–709.
Ahn VE, Faull KF, Whitelegge JP, Fluharty AL, Prive GG. Crystal structure of saposin B reveals a dimeric shell for lipid binding. Proc Natl Acad Sci U S A. 2003;100(1):38–43.
Akiyama H, Kobayashi S, Hirabayashi Y, Murakami-Murofushi K. Cholesterol glucosylation is catalyzed by transglucosylation reaction of beta-glucosidase 1. Biochem Biophys Res Commun. 2013;441(4):838–43.
Alecu I, Tedeschi A, Behler N, Wunderling K, Lamberz C, Lauterbach MA, et al. Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction. J Lipid Res. 2017;58(1):42–59.
Ali M, Fritsch J, Zigdon H, Pewzner-Jung Y, Schutze S, Futerman AH. Altering the sphingolipid acyl chain composition prevents LPS/GLN-mediated hepatic failure in mice by disrupting TNFR1 internalization. Cell Death Dis. 2013;4:e929.
Ali M, Saroha A, Pewzner-Jung Y, Futerman AH. LPS-mediated septic shock is augmented in ceramide synthase 2 null mice due to elevated activity of TNFalpha-converting enzyme. FEBS Lett. 2015;589(17):2213–7.
Allende ML, Proia RL. Simplifying complexity: genetically resculpting glycosphingolipid synthesis pathways in mice to reveal function. Glycoconj J. 2014;31(9):613–22.
Anheuser S, Breiden B, Schwarzmann G, Sandhoff K. Membrane lipids regulate ganglioside GM2 catabolism and GM2 activator protein activity. J Lipid Res. 2015;56(9):1747–61.
Anheuser S, Breiden B, Sandhoff K. Ganglioside GM2 catabolism is inhibited by storage compounds of mucopolysaccharidoses and by cationic amphiphilic drugs. Mol Genet Metab. 2019a;128(1–2):75–83.
Anheuser S, Breiden B, Sandhoff K. Membrane lipids and their degradation compounds control GM2 catabolism at intralysosomal luminal vesicles. J Lipid Res. 2019b;60(6):1099–111.
Annunziata I, Patterson A, Helton D, Hu H, Moshiach S, Gomero E, et al. Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-beta secretion via deregulated lysosomal exocytosis. Nat Commun. 2013;4:2734.
Annunziata I, Sano R, d'Azzo A. Mitochondria-associated ER membranes (MAMs) and lysosomal storage diseases. Cell Death Dis. 2018;9(3):328.
Ashida H, Li YT. Glycosidases: inborn errors of glycosphingolipid catabolism. Adv Neurobiol. 2014;9:463–84.
Aureli M, Samarani M, Murdica V, Mauri L, Loberto N, Bassi R, et al. Gangliosides and cell surface ganglioside glycohydrolases in the nervous system. Adv Neurobiol. 2014;9:223–44.
Bagatolli LA, Gratton E. Two photon fluorescence microscopy of coexisting lipid domains in giant unilamellar vesicles of binary phospholipid mixtures. Biophys J. 2000;78(1):290–305.
Barraud P, Stott S, Mollgard K, Parmar M, Bjorklund A. In vitro characterization of a human neural progenitor cell coexpressing SSEA4 and CD133. J Neurosci Res. 2007;85(2):250–9.
Barron K, Ogretmen B, Krupenko N. Ceramide synthase 6 mediates sex-specific metabolic response to dietary folic acid in mice. J Nutr Biochem. 2021;98:108832.
Barthelmes J, de Bazo AM, Pewzner-Jung Y, Schmitz K, Mayer CA, Foerch C, et al. Lack of ceramide synthase 2 suppresses the development of experimental autoimmune encephalomyelitis by impairing the migratory capacity of neutrophils. Brain Behav Immun. 2015;46:280–92.
Belarbi K, Cuvelier E, Bonte MA, Desplanque M, Gressier B, Devos D, et al. Glycosphingolipids and neuroinflammation in Parkinson’s disease. Mol Neurodegener. 2020;15(1):59.
Bickert A, Kern P, van Uelft M, Herresthal S, Ulas T, Gutbrod K, et al. Inactivation of ceramide synthase 2 catalytic activity in mice affects transcription of genes involved in lipid metabolism and cell division. Biochim Biophys Acta. 2018;1863(7):734–49.
Bierfreund U, Lemm T, Hoffmann A, Uhlhorn-Dierks G, Childs RA, Yuen CT, et al. Recombinant GM2-activator protein stimulates in vivo degradation of GA2 in GM2 gangliosidosis AB variant fibroblasts but exhibits no detectable binding of GA2 in an in vitro assay. Neurochem Res. 1999;24(2):295–300.
Blumenreich S, Yaacobi C, Vardi A, Barav OB, Vitner EB, Park H, et al. Substrate reduction therapy using Genz-667161 reduces levels of pathogenic components in a mouse model of neuronopathic forms of Gaucher disease. J Neurochem. 2021;156(5):692–701.
Boccuto L, Aoki K, Flanagan-Steet H, Chen CF, Fan X, Bartel F, et al. A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation. Hum Mol Genet. 2014;23(2):418–33.
Bonten E, van der Spoel A, Fornerod M, Grosveld G, d'Azzo A. Characterization of human lysosomal neuraminidase defines the molecular basis of the metabolic storage disorder sialidosis. Genes Dev. 1996;10(24):3156–69.
Bottai D, Adami R, Ghidoni R. The crosstalk between glycosphingolipids and neural stem cells. J Neurochem. 2019;148(6):698–711.
Boutry M, Branchu J, Lustremant C, Pujol C, Pernelle J, Matusiak R, et al. Inhibition of lysosome membrane recycling causes accumulation of gangliosides that contribute to neurodegeneration. Cell Rep. 2018;23(13):3813–26.
Bowman EA, Walterfang M, Abel L, Desmond P, Fahey M, Velakoulis D. Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann-Pick disease type C patients treated with miglustat. J Neurol. 2015;262(9):2106–14.
Boyden LM, Vincent NG, Zhou J, Hu R, Craiglow BG, Bayliss SJ, et al. Mutations in KDSR cause recessive progressive symmetric erythrokeratoderma. Am J Hum Genet. 2017;100(6):978–84.
Bradova V, Smid F, Ulrich-Bott B, Roggendorf W, Paton BC, Harzer K. Prosaposin deficiency: further characterization of the sphingolipid activator protein-deficient sibs. Multiple glycolipid elevations (including lactosylceramidosis), partial enzyme deficiencies and ultrastructure of the skin in this generalized sphingolipid storage disease. Hum Genet. 1993;92(2):143–52.
Braun PE, Snell EE. Biosynthesis of sphingolipid bases. II. Keto intermediates in synthesis of sphingosine and dihydrosphingosine by cell-free extracts of Hansenula ciferri. J Biol Chem. 1968;243(14):3775–83.
Braun PE, Morell P, Radin NS. Synthesis of C18- and C20-dihydrosphingosines, ketodihydrosphingosines, and ceramides by microsomal preparations from mouse brain. J Biol Chem. 1970;245(2):335–41.
Breiden B, Sandhoff K. The role of sphingolipid metabolism in cutaneous permeability barrier formation. Biochim Biophys Acta. 2014;1841(3):441–52.
Breiden B, Sandhoff K. Emerging mechanisms of drug-induced phospholipidosis. Biol Chem. 2019a;401(1):31–46.
Breiden B, Sandhoff K. Lysosomal glycosphingolipid storage diseases. Annu Rev Biochem. 2019b;88:461–85.
Breiden B, Sandhoff K. Mechanism of secondary ganglioside and lipid accumulation in lysosomal disease. Int J Mol Sci. 2020;21(7):2566.
Breiden B, Sandhoff K. Acid sphingomyelinase, a lysosomal and secretory phospholipase C, is key for cellular phospholipid catabolism. Int J Mol Sci. 2021;22(16)
Breslow DK, Collins SR, Bodenmiller B, Aebersold R, Simons K, Shevchenko A, et al. Orm family proteins mediate sphingolipid homeostasis. Nature. 2010;463(7284):1048–53.
Brochner CB, Mollgard K. SSEA-4 and YKL-40 positive progenitor subtypes in the subventricular zone of develo** human neocortex. Glia. 2016;64(1):90–104.
Budani M, Auray-Blais C, Lingwood C. ATP-binding cassette transporters mediate differential biosynthesis of glycosphingolipid species. J Lipid Res. 2021;62:100128.
Burkhardt JK, Huttler S, Klein A, Mobius W, Habermann A, Griffiths G, et al. Accumulation of sphingolipids in SAP-precursor (prosaposin)-deficient fibroblasts occurs as intralysosomal membrane structures and can be completely reversed by treatment with human SAP-precursor. Eur J Cell Biol. 1997;73(1):10–8.
Chester MA. Nomenclature of glycolipids. Pure Appl Chem. 1997;69(12):2475–87.
Chinnapen DJ, Hsieh WT, te Welscher YM, Saslowsky DE, Kaoutzani L, Brandsma E, et al. Lipid sorting by ceramide structure from plasma membrane to ER for the cholera toxin receptor ganglioside GM1. Dev Cell. 2012;23(3):573–86.
Chumpen Ramirez S, Ruggiero FM, Daniotti JL, Valdez Taubas J. Ganglioside glycosyltransferases are S-acylated at conserved cysteine residues involved in homodimerisation. Biochem J. 2017;474(16):2803–16.
Collins BE, Yang LJ, Mukhopadhyay G, Filbin MT, Kiso M, Hasegawa A, et al. Sialic acid specificity of myelin-associated glycoprotein binding. J Biol Chem. 1997;272(2):1248–55.
Conzelmann E, Sandhoff K. AB variant of infantile GM2 gangliosidosis: deficiency of a factor necessary for stimulation of hexosaminidase A-catalyzed degradation of ganglioside GM2 and glycolipid GA2. Proc Natl Acad Sci U S A. 1978;75(8):3979–83.
Cosden M, **n S, Yao L, Gretzula CA, Kandebo M, Toolan D, et al. A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy. Neurobiol Dis. 2021;159:105507.
Cuatrecasas P. Gangliosides and membrane receptors for cholera toxin. Biochemistry. 1973;12(18):3558–66.
Cui M, Ying R, Jiang X, Li G, Zhang X, Zheng J, et al. A model of hereditary sensory and autonomic neuropathy type 1 reveals a role of glycosphingolipids in neuronal polarity. J Neurosci. 2019;39(29):5816–34.
Cutillo G, Saariaho AH, Meri S. Physiology of gangliosides and the role of antiganglioside antibodies in human diseases. Cell Mol Immunol. 2020;17(4):313–22.
D’Angelo G, Polishchuk E, Di Tullio G, Santoro M, Di Campli A, Godi A, et al. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature. 2007;449(7158):62–7.
d’Azzo A, Bonten E. Molecular mechanisms of pathogenesis in a glycosphingolipid and a glycoprotein storage disease. Biochem Soc Trans. 2010;38(6):1453–7.
d’Azzo A, Machado E, Annunziata I. Pathogenesis, emerging therapeutic targets and treatment in sialidosis. Expert Opin Orphan Drugs. 2015;3(5):491–504.
d’Azzo A, Andria G, Bonten E, Annunziata I. Galactosialidosis. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill Education; 2019.
Daniotti JL, Iglesias-Bartolome R. Metabolic pathways and intracellular trafficking of gangliosides. IUBMB Life. 2011;63(7):513–20.
Daniotti JL, Pedro MP, Valdez Taubas J. The role of S-acylation in protein trafficking. Traffic. 2017;18(11):699–710.
Davis SE, Roth JR, Aljabi Q, Hakim AR, Savell KE, Day JJ, et al. Delivering progranulin to neuronal lysosomes protects against excitotoxicity. J Biol Chem. 2021;297(3):100993.
De Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966;28:435–92.
Desnick RJ, Ioannou YA, Eng CM. α-Galactosidase a deficiency: fabry disease. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill Education; 2019.
Doering T, Holleran WM, Potratz A, Vielhaber G, Elias PM, Suzuki K, et al. Sphingolipid activator proteins are required for epidermal permeability barrier formation. J Biol Chem. 1999;274(16):11038–45.
Dong M, Tepp WH, Liu H, Johnson EA, Chapman ER. Mechanism of botulinum neurotoxin B and G entry into hippocampal neurons. J Cell Biol. 2007;179(7):1511–22.
Dunn TM, Tifft CJ, Proia RL. A perilous path: the inborn errors of sphingolipid metabolism. J Lipid Res. 2019;60(3):475–83.
Durrie R, Saito M, Rosenberg A. Endogenous glycosphingolipid acceptor specificity of sialosyltransferase systems in intact Golgi membranes, synaptosomes, and synaptic plasma membranes from rat brain. Biochemistry. 1988;27(10):3759–64.
Ebel P, Vom Dorp K, Petrasch-Parwez E, Zlomuzica A, Kinugawa K, Mariani J, et al. Inactivation of ceramide synthase 6 in mice results in an altered sphingolipid metabolism and behavioral abnormalities. J Biol Chem. 2013;288(29):21433–47.
Ebel P, Imgrund S, Vom Dorp K, Hofmann K, Maier H, Drake H, et al. Ceramide synthase 4 deficiency in mice causes lipid alterations in sebum and results in alopecia. Biochem J. 2014;461(1):147–58.
Eberle M, Ebel P, Wegner MS, Mannich J, Tafferner N, Ferreiros N, et al. Regulation of ceramide synthase 6 in a spontaneous experimental autoimmune encephalomyelitis model is sex dependent. Biochem Pharmacol. 2014;92(2):326–35.
Eckl KM, Tidhar R, Thiele H, Oji V, Hausser I, Brodesser S, et al. Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length. J Invest Dermatol. 2013;133(9):2202–11.
Eidels L, Proia RL, Hart DA. Membrane receptors for bacterial toxins. Microbiol Rev. 1983;47(4):596–620.
El-Hindi K, Brachtendorf S, Hartel JC, Oertel S, Birod K, Trautmann S, et al. Ceramide synthase 5 deficiency aggravates dextran sodium sulfate-induced colitis and colon carcinogenesis and impairs T-cell activation. Cancers (Basel). 2020;12(7):1753.
Eliyahu E, Shtraizent N, Shalgi R, Schuchman EH. Construction of conditional acid ceramidase knockout mice and in vivo effects on oocyte development and fertility. Cell Physiol Biochem. 2012;30(3):735–48.
Elojeimy S, Holman DH, Liu X, El-Zawahry A, Villani M, Cheng JC, et al. New insights on the use of desipramine as an inhibitor for acid ceramidase. FEBS Lett. 2006;580(19):4751–6.
Enkavi G, Mikkolainen H, Gungor B, Ikonen E, Vattulainen I. Concerted regulation of npc2 binding to endosomal/lysosomal membranes by bis(monoacylglycero)phosphate and sphingomyelin. PLoS Comput Biol. 2017;13(10):e1005831.
Enomoto A, Omae F, Miyazaki M, Kozutsumi Y, Yubisui T, Suzuki A. Dihydroceramide: sphinganine C-4-hydroxylation requires Des2 hydroxylase and the membrane form of cytochrome b5. Biochem J. 2006;397(2):289–95.
Eskelinen EL, Tanaka Y, Saftig P. At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol. 2003;13(3):137–45.
Farr S, Niehoff M, Banerjee S, Nguyen A. Progranulin enhances memory in normal aging and Alzheimer’s disease mice. FASEB J. 2021;35(S1):35.
Farrer RG, Quarles RH. Expression of sulfated gangliosides in the central nervous system. J Neurochem. 1997;68(2):878–81.
Ferraz MJ, Marques ARA, Appelman MD, Verhoek M, Strijland A, Mirzaian M, et al. Lysosomal glycosphingolipid catabolism by acid ceramidase: formation of glycosphingoid bases during deficiency of glycosidases. FEBS Lett. 2016;590(6):716–25.
Finsterwald C, Dias S, Magistretti PJ, Lengacher S. Ganglioside GM1 targets astrocytes to stimulate cerebral energy metabolism. Front Pharmacol. 2021;12:653842.
Fischer G, Jatzkewitz H. The activator of cerebroside sulphatase. Purification from human liver and identification as a protein. Hoppe Seylers Z Physiol Chem. 1975;356(5):605–13.
Fischer G, Jatzkewitz H. The activator of cerebroside-sulphatase. A model of the activation. Biochim Biophys Acta. 1978;528(1):69–76.
Florey O, Overholtzer M. Autophagy proteins in macroendocytic engulfment. Trends Cell Biol. 2012;22(7):374–80.
Fragaki K, Ait-El-Mkadem S, Chaussenot A, Gire C, Mengual R, Bonesso L, et al. Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency. Eur J Hum Genet. 2013;21(5):528–34.
Fredriksen K, Aivazidis S, Sharma K, Burbidge KJ, Pitcairn C, Zunke F, et al. Pathological α-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of α-syn in vivo. Proc Natl Acad Sci. 2021;118(50):e2108489118.
Furst W, Sandhoff K. Activator proteins and topology of lysosomal sphingolipid catabolism. Biochim Biophys Acta. 1992;1126(1):1–16.
Furukawa K, Hamamura K, Ohkawa Y, Ohmi Y, Furukawa K. Disialyl gangliosides enhance tumor phenotypes with differential modalities. Glycoconj J. 2012;29(8-9):579–84.
Furukawa K, Ohmi Y, Ohkawa Y, Tajima O, Furukawa K. Glycosphingolipids in the regulation of the nervous system. Adv Neurobiol. 2014;9:307–20.
Furukawa K, Ohmi Y, Tajima O, Ohkawa Y, Kondo Y, Shuting J, et al. Gangliosides in inflammation and neurodegeneration. Prog Mol Biol Transl Sci. 2018;156:265–87.
Furuya S, Hashikawa T, Hirabayashi Y. Restricted occurrence of an unusual ganglioside GD1 alpha in rat brain and its possible involvement in dendritic growth of cerebellar Purkinje neurons. J Neurosci Res. 1996;44(1):73–83.
Futerman AH, Pagano RE. Determination of the intracellular sites and topology of glucosylceramide synthesis in rat liver. Biochem J. 1991;280(Pt 2):295–302.
Gallala HD, Sandhoff K. Biological function of the cellular lipid BMP-BMP as a key activator for cholesterol sorting and membrane digestion. Neurochem Res. 2011;36(9):1594–600.
Garrido-Arandia M, Cuevas-Zuviria B, Diaz-Perales A, Pacios LF. A comparative study of human saposins. Molecules. 2018;23(2):422.
Geeraert L, Mannaerts GP, van Veldhoven PP. Conversion of dihydroceramide into ceramide: involvement of a desaturase. Biochem J. 1997;327(Pt 1):125–32.
Giehl A, Lemm T, Bartelsen O, Sandhoff K, Blume A. Interaction of the GM2-activator protein with phospholipid-ganglioside bilayer membranes and with monolayers at the air-water interface. Eur J Biochem. 1999;261(3):650–8.
Gieselmann V, Ingeborg K-M. Metachromatic leukodystrophy. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill Education; 2019.
Gillard BK, Harrell RG, Marcus DM. Pathways of glycosphingolipid biosynthesis in SW13 cells in the presence and absence of vimentin intermediate filaments. Glycobiology. 1996;6(1):33–42.
Ginkel C, Hartmann D, Vom Dorp K, Zlomuzica A, Farwanah H, Eckhardt M, et al. Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelin associated glycoprotein in oligodendrocytes. J Biol Chem. 2012;287(50):41888–902.
Giraudo CG, Maccioni HJ. Ganglioside glycosyltransferases organize in distinct multienzyme complexes in CHO-K1 cells. J Biol Chem. 2003;278(41):40262–71.
Gosejacob D, Jager PS, Vom Dorp K, Frejno M, Carstensen AC, Kohnke M, et al. Ceramide synthase 5 is essential to maintain C16:0 ceramide pools and contributes to the development of diet induced obesity. J Biol Chem. 2016;291(13) 6989:–7003.
Grabowski GA, Kolodny EH, Weinreb NJ, Rosenbloom BE, Prakash-Cheng A, Kaplan P, et al. Gaucher disease: phenotypic and genetic variation. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill Education; 2019a.
Grabowski GA, Petsko GA, Kolodny EH. Gaucher disease. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill Education; 2019b.
Graf CGF, Schulz C, Schmalzlein M, Heinlein C, Monnich M, Perkams L, et al. Synthetic glycoforms reveal carbohydrate-dependent bioactivity of human saposin D. Angew Chem Int Ed Engl. 2017;56(19):5252–7.
Grassi S, Chiricozzi E, Mauri L, Sonnino S, Prinetti A. Sphingolipids and neuronal degeneration in lysosomal storage disorders. J Neurochem. 2019;148(5):600–11.
Gravel RA, Kaback MM, Proia RL, Sandhoff K, Suzuki K, Suzuki K. The GM2 gangliosidoses. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill Education; 2019.
Gupta SD, Gable K, Alexaki A, Chandris P, Proia RL, Dunn TM, et al. Expression of the ORMDLS, modulators of serine palmitoyltransferase, is regulated by sphingolipids in mammalian cells. J Biol Chem. 2015;290(1):90–8.
Hakomori S. Glycosphingolipids in cellular interaction, differentiation, and oncogenesis. Annu Rev Biochem. 1981;50:733–64.
Hakomori SI, Handa K. GM3 and cancer. Glycoconj J. 2015;32(1-2):1–8.
Hamark C, Berntsson RP, Masuyer G, Henriksson LM, Gustafsson R, Stenmark P, et al. Glycans confer specificity to the recognition of ganglioside receptors by botulinum neurotoxin A. J Am Chem Soc. 2017;139(1):218–30.
Hammerschmidt P, Ostkotte D, Nolte H, Gerl MJ, Jais A, Brunner HL, et al. CerS6-derived sphingolipids interact with Mff and promote mitochondrial fragmentation in obesity. Cell. 2019;177(6):1536–52 e23.
Han G, Gupta SD, Gable K, Niranjanakumari S, Moitra P, Eichler F, et al. Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proc Natl Acad Sci U S A. 2009;106(20):8186–91.
Han S, Lone MA, Schneiter R, Chang A. Orm1 and Orm2 are conserved endoplasmic reticulum membrane proteins regulating lipid homeostasis and protein quality control. Proc Natl Acad Sci U S A. 2010;107(13):5851–6.
Handa K, Hakomori SI. Carbohydrate to carbohydrate interaction in development process and cancer progression. Glycoconj J. 2012;29(8-9):627–37.
Hara A, Kitazawa N, Taketomi T. Abnormalities of glycosphingolipids in mucopolysaccharidosis type III B. J Lipid Res. 1984;25(2):175–84.
Harlalka GV, Lehman A, Chioza B, Baple EL, Maroofian R, Cross H, et al. Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis. Brain. 2013;136(Pt 12):3618–24.
Harmon JM, Bacikova D, Gable K, Gupta SD, Han G, Sengupta N, et al. Topological and functional characterization of the ssSPTs, small activating subunits of serine palmitoyltransferase. J Biol Chem. 2013;288(14):10144–53.
Harzer K, Paton BC, Poulos A, Kustermann-Kuhn B, Roggendorf W, Grisar T, et al. Sphingolipid activator protein deficiency in a 16-week-old atypical Gaucher disease patient and his fetal sibling: biochemical signs of combined sphingolipidoses. Eur J Pediatr. 1989;149(1):31–9.
Helke K, Angel P, Lu P, Garrett-Mayer E, Ogretmen B, Drake R, et al. Ceramide synthase 6 deficiency enhances inflammation in the DSS model of colitis. Sci Rep. 2018;8(1):1627.
Hla T, Kolesnick R. C16:0-ceramide signals insulin resistance. Cell Metab. 2014;20(5):703–5.
Hoglinger D, Haberkant P, Aguilera-Romero A, Riezman H, Porter FD, Platt FM, et al. Intracellular sphingosine releases calcium from lysosomes. elife. 2015;4:e10616.
Hornemann T. Mini review: lipids in peripheral nerve disorders. Neurosci Lett. 2021;740:135455.
Hornemann T, Penno A, Rutti MF, Ernst D, Kivrak-Pfiffner F, Rohrer L, et al. The SPTLC3 subunit of serine palmitoyltransferase generates short chain sphingoid bases. J Biol Chem. 2009;284(39):26322–30.
Hulkova H, Cervenkova M, Ledvinova J, Tochackova M, Hrebicek M, Poupetova H, et al. A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation. Hum Mol Genet. 2001;10(9):927–40.
Hurwitz R, Ferlinz K, Sandhoff K. The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts. Biol Chem Hoppe Seyler. 1994;375(7):447–50.
Iber H, Sandhoff K. Identity of GD1C, GT1a and GQ1b synthase in Golgi vesicles from rat liver. FEBS Lett. 1989;254(1-2):124–8.
Iber H, van Echten G, Sandhoff K. Substrate specificity of alpha 2↔3-sialyltransferases in ganglioside biosynthesis of rat liver golgi. Eur J Biochem. 1991;195(1):115–20.
Iber H, Zacharias C, Sandhoff K. The c-series gangliosides GT3, GT2 and GP1c are formed in rat liver Golgi by the same set of glycosyltransferases that catalyse the biosynthesis of asialo-, a- and b-series gangliosides. Glycobiology. 1992;2(2):137–42.
Ica R, Munteanu CV, Vukelic Z, Zamfir AD. High-resolution mass spectrometry reveals a complex ganglioside pattern and novel polysialylated structures associated with the human motor cortex. Eur J Mass Spectrom (Chichester). 2021:14690667211040912.
Ichikawa S, Ozawa K, Hirabayashi Y. Molecular cloning and characterization of the mouse ceramide glucosyltransferase gene. Biochem Biophys Res Commun. 1998;253(3):707–11.
Igisu H, Suzuki K. Progressive accumulation of toxic metabolite in a genetic leukodystrophy. Science. 1984;224(4650):753–5.
Imgrund S, Hartmann D, Farwanah H, Eckhardt M, Sandhoff R, Degen J, et al. Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. J Biol Chem. 2009;284(48):33549–60.
Ingolfsson HI, Melo MN, van Eerden FJ, Arnarez C, Lopez CA, Wassenaar TA, et al. Lipid organization of the plasma membrane. J Am Chem Soc. 2014;136(41):14554–9.
Ingolfsson HI, Carpenter TS, Bhatia H, Bremer PT, Marrink SJ, Lightstone FC. Computational lipidomics of the neuronal plasma membrane. Biophys J. 2017;113(10):2271–80.
Inokuchi J. Membrane microdomains and insulin resistance. FEBS Lett. 2010;584(9):1864–71.
Inokuchi J, Nagafuku M, Ohno I, Suzuki A. Distinct selectivity of gangliosides required for CD4(+) T and CD8(+) T cell activation. Biochim Biophys Acta. 2015;1851(1):98–106.
Ishii A, Ohta M, Watanabe Y, Matsuda K, Ishiyama K, Sakoe K, et al. Expression cloning and functional characterization of human cDNA for ganglioside GM3 synthase. J Biol Chem. 1998;273(48):31652–5.
Itokazu Y, Wang J, Yu RK. Gangliosides in nerve cell specification. Prog Mol Biol Transl Sci. 2018;156:241–63.
Itokazu Y, Fuchigami T, Morgan JC, Yu RK. Intranasal infusion of GD3 and GM1 gangliosides downregulates alpha-synuclein and controls tyrosine hydroxylase gene in a PD model mouse. Mol Ther. 2021;29(10):3059–71.
Iwamori M, Shimomura J, Tsuyuhara S, Nagai Y. Gangliosides of various rat tissues: distribution of ganglio-N-tetraose-containing gangliosides and tissue-characteristic composition of gangliosides. J Biochem (Tokyo). 1984;95(3):761–70.
Jatzkewitz H, Sandhoff K. On a biochemically special form of infantile amaurotic idiocy. Biochim Biophys Acta. 1963;70(3):354.
Jeckel D, Karrenbauer A, Burger KN, van Meer G, Wieland F. Glucosylceramide is synthesized at the cytosolic surface of various Golgi subfractions. J Cell Biol. 1992;117(2):259–67.
Jennemann R, Sandhoff R, Wang S, Kiss E, Gretz N, Zuliani C, et al. Cell-specific deletion of glucosylceramide synthase in brain leads to severe neural defects after birth. Proc Natl Acad Sci U S A. 2005;102(35):12459–64.
Jennemann R, Rothermel U, Wang S, Sandhoff R, Kaden S, Out R, et al. Hepatic glycosphingolipid deficiency and liver function in mice. Hepatology. 2010;51(5):1799–809.
Jennemann R, Kaden S, Sandhoff R, Nordstrom V, Wang S, Volz M, et al. Glycosphingolipids are essential for intestinal endocytic function. J Biol Chem. 2012a;287:32598–616.
Jennemann R, Rabionet M, Gorgas K, Epstein S, Dalpke A, Rothermel U, et al. Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum Mol Genet. 2012b;21(3):586–608.
Jiang JC, Kirchman PA, Zagulski M, Hunt J, Jazwinski SM. Homologs of the yeast longevity gene LAG1 in Caenorhabditis elegans and human. Genome Res. 1998;8(12):1259–72.
Jo A, Lee Y, Kam TI, Kang SU, Neifert S, Karuppagounder SS, et al. PARIS farnesylation prevents neurodegeneration in models of Parkinson’s disease. Sci Transl Med. 2021;13(604):eaax8891.
Kaltner H, Abad-Rodriguez J, Corfield AP, Kopitz J, Gabius HJ. The sugar code: letters and vocabulary, writers, editors and readers and biosignificance of functional glycan-lectin pairing. Biochem J. 2019;476(18):2623–55.
Kannagi R, Cochran NA, Ishigami F, Hakomori S, Andrews PW, Knowles BB, et al. Stage-specific embryonic antigens (SSEA-3 and -4) are epitopes of a unique globo-series ganglioside isolated from human teratocarcinoma cells. EMBO J. 1983;2(12):2355–61.
Kaufman B, Basu S, Roseman S. Enzymatic synthesis of disialogangliosides from monosialogangliosides by sialyltransferases from embryonic chicken brain. J Biol Chem. 1968;243(21):5804–7.
Keenan TW, Morre DJ, Basu S, Ganglioside biosynthesis. Concentration of glycosphingolipid glycosyltransferases in Golgi apparatus from rat liver. J Biol Chem. 1974;249(1):310–5.
Keranen A. Fatty acids and long-chain bases of gangliosides of human gastrointestinal mucosa. Chem Phys Lipids. 1976;17(1):14–21.
Kihara A. Synthesis and degradation pathways, functions, and pathology of ceramides and epidermal acylceramides. Prog Lipid Res. 2016;63:50–69.
Kim YR, Volpert G, Shin KO, Kim SY, Shin SH, Lee Y, et al. Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate-induced colitis in mice due to increased intestinal permeability. J Cell Mol Med. 2017;21(12):3565–78.
Kim S, Yun SP, Lee S, Umanah GE, Bandaru VVR, Yin X, et al. GBA1 deficiency negatively affects physiological alpha-synuclein tetramers and related multimers. Proc Natl Acad Sci U S A. 2018;115(4):798–803.
Kishimoto Y, Radin NS. Determination of brain gangliosides by determination of ganglioside stearic acid. J Lipid Res. 1966;7(1):141–5.
Klenk E. Niemann-Pick’sche Krankheit und Amaurotische Idiotie. Hoppe Seylers Z Physiol Chem. 1939;262:128–43.
Klenk E. Über die Ganglioside, eine neue Gruppe von zuckerhaltigen Gehirnlipoiden. Hoppe Seylers Z Physiol Chem. 1942;273(1-2):76–86.
Klenk E, Hof L, Georgias K. Studies on brain gangliosides. Hoppe Seylers Z Physiol Chem. 1967;348(2):149–66.
Kobayashi T, Beuchat MH, Lindsay M, Frias S, Palmiter RD, Sakuraba H, et al. Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nat Cell Biol. 1999;1(2):113–8.
Kok JW, Eskelinen S, Hoekstra K, Hoekstra D. Salvage of glucosylceramide by recycling after internalization along the pathway of receptor-mediated endocytosis. Proc Natl Acad Sci U S A. 1989;86(24):9896–900.
Kolter T, Sandhoff K. Sphingolipids – their metabolic pathways and the pathobiochemistry of neurodegenerative diseases. Angew Chem Int Edit. 1999;38(11):1532–68.
Kolter T, Sandhoff K. Principles of lysosomal membrane digestion-stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids. Annu Rev Cell Dev Biol. 2005;21:81–103.
Kolter T, Sandhoff K. Sphingolipid metabolism diseases. Biochim Biophys Acta. 2006;1758(12):2057–79.
Kolter T, Proia RL, Sandhoff K. Combinatorial ganglioside biosynthesis. J Biol Chem. 2002;277(29):25859–62.
Kolter T, Winau F, Schaible UE, Leippe M, Sandhoff K. Lipid-binding proteins in membrane digestion, antigen presentation, and antimicrobial defense. J Biol Chem. 2005;280(50):41125–8.
Kolzer M, Werth N, Sandhoff K. Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine. FEBS Lett. 2004;559(1-3):96–8.
Kono M, Yoshida Y, Kojima N, Tsuji S. Molecular cloning and expression of a fifth type of alpha2,8-sialyltransferase (ST8Sia V). Its substrate specificity is similar to that of SAT-V/III, which synthesize GD1c, GT1a, GQ1b and GT3. J Biol Chem. 1996;271(46):29366–71.
Kotani M, Tai T. An immunohistochemical technique with a series of monoclonal antibodies to gangliosides: their differential distribution in the rat cerebellum. Brain Res Brain Res Protoc. 1997;1(2):152–6.
Kotani M, Kawashima I, Ozawa H, Terashima T, Tai T. Immunohistochemical localization of major gangliosides in rat cerebellum. Proc Jpn Acad Ser B Phys Biol Sci. 1992;68(7):109–13.
Kotani M, Kawashima I, Ozawa H, Terashima T, Tai T. Differential distribution of major gangliosides in rat central nervous system detected by specific monoclonal antibodies. Glycobiology. 1993;3(2):137–46.
Kotani M, Kawashima I, Ozawa H, Ogura K, Ishizuka I, Terashima T, et al. Immunohistochemical localization of minor gangliosides in the rat central nervous system. Glycobiology. 1994;4(6):855–65.
Kotani M, Terashima T, Tai T. Developmental changes of ganglioside expressions in postnatal rat cerebellar cortex. Brain Res. 1995;700(1–2):40–58.
Kuhn R, Wiegandt H. Die Konstitution Der Ganglio-N-Tetraose Und Des Gangliosids Gi. Chem Ber-Recl. 1963;96(3):866.
Ladisch S, Liu Y. Dynamic aspects of neural tumor gangliosides. Adv Neurobiol. 2014;9:501–15.
Lai M, Realini N, La Ferla M, Passalacqua I, Matteoli G, Ganesan A, et al. Complete acid ceramidase ablation prevents cancer-initiating cell formation in melanoma cells. Sci Rep. 2017;7(1):7411.
Lannert H, Bunning C, Jeckel D, Wieland FT. Lactosylceramide is synthesized in the lumen of the Golgi apparatus. FEBS Lett. 1994;342(1):91–6.
Ledeen R, Wu G. New findings on nuclear gangliosides: overview on metabolism and function. J Neurochem. 2011;116(5):714–20.
Ledeen R, Wu G. Gangliosides of the nervous system. In: Sonnino S, Prinetti A, editors. Gangliosides: methods and protocols. Methods Mol Biol. New York: Springer New York; 2018a. p. 19–55.
Ledeen RW, Wu G. Gangliosides, alpha-Synuclein, and Parkinson’s disease. Prog Mol Biol Transl Sci. 2018b;156:435–54.
Ledeen RW, Yu RK, Eng LF. Gangliosides of human myelin: sialosylgalactosylceramide (G7) as a major component. J Neurochem. 1973;21(4):829–39.
Ledeen RW, Wu G, Andre S, Bleich D, Huet G, Kaltner H, et al. Beyond glycoproteins as galectin counterreceptors: tumor-effector T cell growth control via ganglioside GM1 [corrected]. Ann N Y Acad Sci. 2012;1253:206–21.
Lee HR, Choi SQ. Sphingomyelinase-mediated multitimescale clustering of ganglioside GM1 in heterogeneous lipid membranes. Adv Sci (Weinh). 2021:e2101766.
Lee JY, Marian OC, Don AS. Defective lysosomal lipid catabolism as a common pathogenic mechanism for dementia. NeuroMolecular Med. 2021;23(1):1–24.
Levade T, Sandhoff K, Schulze H, Medin JA. Acid ceramidase deficiency: farber lipogranulomatosis. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill Education; 2019.
Levy M, Futerman AH. Mammalian ceramide synthases. IUBMB Life. 2010;62(5):347–56.
Li TA, Schnaar RL. Congenital disorders of ganglioside biosynthesis. Prog Mol Biol Transl Sci. 2018;156:63–82.
Lingwood CA. Glycolipid receptors for verotoxin and Helicobacter pylori: role in pathology. Biochim Biophys Acta. 1999;1455(2-3):375–86.
Linke T, Wilkening G, Sadeghlar F, Mozcall H, Bernardo K, Schuchman E, et al. Interfacial regulation of acid ceramidase activity. Stimulation of ceramide degradation by lysosomal lipids and sphingolipid activator proteins. J Biol Chem. 2001;276(8):5760–8.
Lipina C, Hundal HS. Ganglioside GM3 as a gatekeeper of obesity-associated insulin resistance: evidence and mechanisms. FEBS Lett. 2015;589(21):3221–7.
Liu Y, Hoffmann A, Grinberg A, Westphal H, McDonald MP, Miller KM, et al. Mouse model of GM2 activator deficiency manifests cerebellar pathology and motor impairment. Proc Natl Acad Sci U S A. 1997;94(15):8138–43.
Lloyd-Evans E, Morgan AJ, He X, Smith DA, Elliot-Smith E, Sillence DJ, et al. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med. 2008;14(11):1247–55.
Locatelli-Hoops S, Remmel N, Klingenstein R, Breiden B, Rossocha M, Schoeniger M, et al. Saposin A mobilizes lipids from low cholesterol and high bis(monoacylglycerol)phosphate-containing membranes: patient variant Saposin A lacks lipid extraction capacity. J Biol Chem. 2006;281(43):32451–60.
Logan T, Simon MJ, Rana A, Cherf GM, Srivastava A, Davis SS, et al. Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. Cell. 2021;184(18):4651–68 e25.
Lucas M, Gershlick DC, Vidaurrazaga A, Rojas AL, Bonifacino JS, Hierro A. Structural mechanism for cargo recognition by the retromer complex. Cell. 2016;167(6):1623–35 e14.
Lullmann H, Lullmann-Rauch R, Wassermann O. Lipidosis induced by amphiphilic cationic drugs. Biochem Pharmacol. 1978;27(8):1103–8.
Lunghi G, Fazzari M, Di Biase E, Mauri L, Chiricozzi E, Sonnino S. The structure of gangliosides hides a code for determining neuronal functions. FEBS Open Bio. 2021;11(12):3193–200.
Maccioni HJ. Glycosylation of glycolipids in the Golgi complex. J Neurochem. 2007;103(Suppl 1):81–90.
Maguire AS, Martin DR. White matter pathology as a barrier to gangliosidosis gene therapy. Front Cell Neurosci. 2021;15:682106.
Marques AR, Mirzaian M, Akiyama H, Wisse P, Ferraz MJ, Gaspar P, et al. Glucosylated cholesterol in mammalian cells and tissues: formation and degradation by multiple cellular beta-glucosidases. J Lipid Res. 2016;57(3):451–63.
Marsching C, Rabionet M, Mathow D, Jennemann R, Kremser C, Porubsky S, et al. Renal sulfatides: sphingoid base-dependent localization and region-specific compensation of CerS2-dysfunction. J Lipid Res. 2014;55(11):2354–69.
Martina JA, Daniotti JL, Maccioni HJ. GM1 synthase depends on N-glycosylation for enzyme activity and trafficking to the Golgi complex. Neurochem Res. 2000;25(5):725–31.
Matsuda J, Vanier MT, Saito Y, Tohyama J, Suzuki K, Suzuki K. A mutation in the saposin A domain of the sphingolipid activator protein (prosaposin) gene results in a late-onset, chronic form of globoid cell leukodystrophy in the mouse. Hum Mol Genet. 2001;10(11):1191–9.
McGonigal R, Willison HJ. The role of gangliosides in the organisation of the node of Ranvier examined in glycosyltransferase transgenic mice. J Anat. 2021. https://doi.org/10.1111/joa.13562.
McGonigal R, Barrie JA, Yao D, Black LE, McLaughlin M, Willison HJ. Neuronally expressed a-series gangliosides are sufficient to prevent the lethal age-dependent phenotype in GM3-only expressing mice. J Neurochem. 2021;158(2):217–32.
Mehl E, Jatzkewitz H. On an enzyme from swine kidneys which cleave cerebroside sulfuric acid esters. Hoppe Seylers Z Physiol Chem. 1963;331:292–4.
Mehl E, Jatzkewitz H. A cerebrosidesulfatase from swine kidney. Hoppe Seylers Z Physiol Chem. 1964;339(1):260–76.
Meier EM, Schwarzmann G, Furst W, Sandhoff K. The human GM2 activator protein. A substrate specific cofactor of beta-hexosaminidase A. J Biol Chem. 1991;266(3):1879–87.
Melton-Celsa AR. Shiga toxin (Stx) classification, structure, and function. Microbiol Spectr. 2014;2(4):EHEC-0024-2013.
Merrill AH Jr, Schmelz EM, Dillehay DL, Spiegel S, Shayman JA, Schroeder JJ, et al. Sphingolipids--the enigmatic lipid class: biochemistry, physiology, and pathophysiology. Toxicol Appl Pharmacol. 1997;142(1):208–25.
Michel C, van Echten-Deckert G, Rother J, Sandhoff K, Wang E, Merrill AH Jr. Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide. J Biol Chem. 1997;272(36):22432–7.
Miyagi T, Yamaguchi K. Mammalian sialidases: physiological and pathological roles in cellular functions. Glycobiology. 2012;22(7):880–96.
Mobius W, Herzog V, Sandhoff K, Schwarzmann G. Gangliosides are transported from the plasma membrane to intralysosomal membranes as revealed by immuno-electron microscopy. Biosci Rep. 1999a;19(4):307–16.
Mobius W, Herzog V, Sandhoff K, Schwarzmann G. Intracellular distribution of a biotin-labeled ganglioside, GM1, by immunoelectron microscopy after endocytosis in fibroblasts. J Histochem Cytochem. 1999b;47(8):1005–14.
Mobius W, van Donselaar E, Ohno-Iwashita Y, Shimada Y, Heijnen HF, Slot JW, et al. Recycling compartments and the internal vesicles of multivesicular bodies harbor most of the cholesterol found in the endocytic pathway. Traffic. 2003;4(4):222–31.
Molander-Melin M, Pernber Z, Franken S, Gieselmann V, Mansson JE, Fredman P. Accumulation of sulfatide in neuronal and glial cells of arylsulfatase A deficient mice. J Neurocytol. 2004;33(4):417–27.
Monti E, Bonten E, D’Azzo A, Bresciani R, Venerando B, Borsani G, et al. Sialidases in vertebrates: a family of enzymes tailored for several cell functions. Adv Carbohydr Chem Biochem. 2010;64:403–79.
Morell P, Radin NS. Specificity in ceramide biosynthesis from long chain bases and various fatty acyl coenzyme A’s by brain microsomes. J Biol Chem. 1970;245(2):342–50.
Mori K, Mahmood MI, Neya S, Matsuzaki K, Hoshino T. Formation of GM1 ganglioside clusters on the lipid membrane containing sphingomyelin and cholesterol. J Phys Chem B. 2012;116(17):5111–21.
Murugesan V, Chuang WL, Liu J, Lischuk A, Kacena K, Lin H, et al. Glucosylsphingosine is a key biomarker of Gaucher disease. Am J Hematol. 2016;91(11):1082–9.
Mutoh T. Neutral glycosphingolipids as neuroinflammatory signaling molecules in neurodegeneration. Trends Glycosci Glycotechnol. 2021;33(191):E5–E10.
Nakamura K, Suzuki M, Inagaki F, Yamakawa T, Suzuki A. A new ganglioside showing choleragenoid-binding activity in mouse spleen. J Biochem. 1987;101(4):825–35.
Nakano M, Hanashima S, Hara T, Kabayama K, Asahina Y, Hojo H, et al. FRET detects lateral interaction between transmembrane domain of EGF receptor and ganglioside GM3 in lipid bilayers. Biochim Biophys Acta Biomembr. 2021;1863(8):183623.
Nalls MA, Blauwendraat C, Sargent L, Vitale D, Leonard H, Iwaki H, et al. Evidence for GRN connecting multiple neurodegenerative diseases. Brain Commun. 2021;3(2):fcab095.
Nazha B, Inal C, Owonikoko TK. Disialoganglioside GD2 expression in solid tumors and role as a target for cancer therapy. Front Oncol. 2020;10:1000.
Nelson MP, Boutin M, Tse TE, Lu H, Haley ED, Ouyang X, et al. The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson’s disease brain in association with the pathologic accumulation of alpha-synuclein. Neurobiol Dis. 2018;110:68–81.
Nguyen AD, Nguyen TA, Martens LH, Mitic LL, Farese RV Jr. Progranulin: at the interface of neurodegenerative and metabolic diseases. Trends Endocrinol Metab. 2013;24(12):597–606.
Nicoli ER, Annunziata I, d’Azzo A, Platt FM, Tifft CJ, Stepien KM. GM1 gangliosidosis-a mini-review. Front Genet. 2021;12:734878.
Nishie T, Hikimochi Y, Zama K, Fukusumi Y, Ito M, Yokoyama H, et al. Beta4-galactosyltransferase-5 is a lactosylceramide synthase essential for mouse extra-embryonic development. Glycobiology. 2010;20(10):1311–22.
Nojiri H, Takaku F, Terui Y, Miura Y, Saito M. Ganglioside GM3: an acidic membrane component that increases during macrophage-like cell differentiation can induce monocytic differentiation of human myeloid and monocytoid leukemic cell lines HL- 60 and U937. Proc Natl Acad Sci U S A. 1986;83(3):782–6.
Nojiri H, Kitagawa S, Nakamura M, Kirito K, Enomoto Y, Saito M. Neolacto-series gangliosides induce granulocytic differentiation of human promyelocytic leukemia cell line HL-60. J Biol Chem. 1988;263(16):7443–6.
Nordstrom V, Willershauser M, Herzer S, Rozman J, von Bohlen und Halbach O, Meldner S, et al. Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis. PLoS Biol. 2013;11(3):e1001506.
Oertel S, Scholich K, Weigert A, Thomas D, Schmetzer J, Trautmann S, et al. Ceramide synthase 2 deficiency aggravates AOM-DSS-induced colitis in mice: role of colon barrier integrity. Cell Mol Life Sci. 2017;74(16):3039–55.
Ohman R. Subcellular fractionation of ganglioside sialidase from human brain. J Neurochem. 1971;18(1):89–95.
Ohmi Y, Ohkawa Y, Yamauchi Y, Tajima O, Furukawa K, Furukawa K. Essential roles of gangliosides in the formation and maintenance of membrane microdomains in brain tissues. Neurochem Res. 2012;37(6):1185–91.
Okuda T. A low-carbohydrate ketogenic diet promotes ganglioside synthesis via the transcriptional regulation of ganglioside metabolism-related genes. Sci Rep. 2019;9(1):7627.
Olsen ASB, Faergeman NJ. Sphingolipids: membrane microdomains in brain development, function and neurological diseases. Open Biol. 2017;7(5):170069.
Omae F, Miyazaki M, Enomoto A, Suzuki M, Suzuki Y, Suzuki A. DES2 protein is responsible for phytoceramide biosynthesis in the mouse small intestine. Biochem J. 2004;379(Pt 3):687–95.
Oninla VO, Breiden B, Babalola JO, Sandhoff K. Acid sphingomyelinase activity is regulated by membrane lipids and facilitates cholesterol transfer by NPC2. J Lipid Res. 2014;55(12):2606–19.
Pan X, De Aragao CBP, Velasco-Martin JP, Priestman DA, Wu HY, Takahashi K, et al. Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides. FASEB J. 2017;31(8):3467–83.
Park JW, Park WJ, Kuperman Y, Boura-Halfon S, Pewzner-Jung Y, Futerman AH. Ablation of very long acyl chain sphingolipids causes hepatic insulin resistance in mice due to altered detergent-resistant membranes. Hepatology. 2013a;57(2):525–32.
Park WJ, Park JW, Erez-Roman R, Kogot-Levin A, Bame JR, Tirosh B, et al. Protection of a ceramide synthase 2 null mouse from drug-induced liver injury: role of gap junction dysfunction and connexin 32 mislocalization. J Biol Chem. 2013b;288(43):30904–16.
Park WJ, Park JW, Merrill AH, Storch J, Pewzner-Jung Y, Futerman AH. Hepatic fatty acid uptake is regulated by the sphingolipid acyl chain length. Biochim Biophys Acta. 2014;1841(12):1754–66.
Park WJ, Brenner O, Kogot-Levin A, Saada A, Merrill AH Jr, Pewzner-Jung Y, et al. Development of pheochromocytoma in ceramide synthase 2 null mice. Endocr Relat Cancer. 2015;22(4):623–32.
Patterson MC, Mengel E, Vanier MT, Schwierin B, Muller A, Cornelisse P, et al. Stable or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann-Pick disease type C: an observational cohort study. Orphanet J Rare Dis. 2015;10:65.
Patterson MC, Vanier MT, Suzuki K, Morris JA, Carstea E, Neufeld EB, et al. Niemann-Pick disease type C: a lipid trafficking disorder. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill Education; 2019.
Paushter DH, Du H, Feng T, Hu F. The lysosomal function of progranulin, a guardian against neurodegeneration. Acta Neuropathol. 2018;136(1):1–17.
Penno A, Reilly MM, Houlden H, Laura M, Rentsch K, Niederkofler V, et al. Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem. 2010;285(15):11178–87.
Peters F, Vorhagen S, Brodesser S, Jakobshagen K, Bruning JC, Niessen CM, et al. Ceramide synthase 4 regulates stem cell homeostasis and hair follicle cycling. J Invest Dermatol. 2015;135(6):1501–9.
Petrache I, Kamocki K, Poirier C, Pewzner-Jung Y, Laviad EL, Schweitzer KS, et al. Ceramide synthases expression and role of ceramide synthase-2 in the lung: insight from human lung cells and mouse models. PLoS One. 2013;8(5):e62968.
Pewzner-Jung Y, Ben-Dor S, Futerman AH. When do lasses (longevity assurance genes) become CerS (ceramide synthases)?: insights into the regulation of ceramide synthesis. J Biol Chem. 2006;281(35):25001–5.
Pewzner-Jung Y, Park H, Laviad EL, Silva LC, Lahiri S, Stiban J, et al. A critical role for ceramide synthase 2 in liver homeostasis: I. alterations in lipid metabolic pathways. J Biol Chem. 2010;285(14):10902–10.
Phaneuf D, Wakamatsu N, Huang JQ, Borowski A, Peterson AC, Fortunato SR, et al. Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases. Hum Mol Genet. 1996;5(1):1–14.
Pilz R, Opálka L, Majcher A, Grimm E, Van Maldergem L, Mihalceanu S, et al. Formation of keto-type ceramides in palmoplantar keratoderma based on biallelic KDSR mutations in patients. Hum Mol Genet. 2022;31(7):1105–14.
Platt FM, d’Azzo A, Davidson BL, Neufeld EF, Tifft CJ. Lysosomal storage diseases. Nat Rev Dis Primers. 2018;4(1):27.
Pohlentz G, Klein D, Schwarzmann G, Schmitz D, Sandhoff K. Both GA2, GM2, and GD2 synthases and GM1b, GD1a, and GT1b synthases are single enzymes in Golgi vesicles from rat liver. Proc Natl Acad Sci U S A. 1988;85(19):7044–8.
Polo G, Burlina AP, Kolamunnage TB, Zampieri M, Dionisi-Vici C, Strisciuglio P, et al. Diagnosis of sphingolipidoses: a new simultaneous measurement of lysosphingolipids by LC-MS/MS. Clin Chem Lab Med. 2017;55(3):403–14.
Posse de Chaves E, Sipione S. Sphingolipids and gangliosides of the nervous system in membrane function and dysfunction. FEBS Lett. 2010;584(9):1748–59.
Pothukuchi P, Agliarulo I, Pirozzi M, Rizzo R, Russo D, Turacchio G, et al. GRASP55 regulates intra-Golgi localization of glycosylation enzymes to control glycosphingolipid biosynthesis. EMBO J. 2021;40(20):e107766.
Pradas I, Jové M, Huynh K, Ingles M, Borras C, Mota-Martorell N, et al. Long-lived humans have a unique plasma sphingolipidome. J Gerontol Ser A. 2022;77(4):728–35.
Prasad VV. Effect of prenatal and postnatal exposure to ethanol on rat central nervous system gangliosides and glycosidases. Lipids. 1992;27(5):344–8.
Preti A, Fiorilli A, Lombardo A, Caimi L, Tettamanti G. Occurrence of sialyltransferase activity in the synaptosomal membranes prepared from calf brain cortex. J Neurochem. 1980;35(2):281–96.
Proia RL. Glycosphingolipid functions: insights from engineered mouse models. Philos Trans R Soc Lond Ser B Biol Sci. 2003;358(1433):879–83.
Quintern LE, Weitz G, Nehrkorn H, Tager JM, Schram AW, Sandhoff K. Acid sphingomyelinase from human urine: purification and characterization. Biochim Biophys Acta. 1987;922(3):323–36.
Quinville BM, Deschenes NM, Ryckman AE, Walia JS. A comprehensive review: sphingolipid metabolism and implications of disruption in sphingolipid homeostasis. Int J Mol Sci. 2021;22(11):5793.
Rabionet M, Gorgas K, Sandhoff R. Ceramide synthesis in the epidermis. Biochim Biophys Acta. 2014;1841(3):422–34.
Rabionet M, Bayerle A, Jennemann R, Heid H, Fuchser J, Marsching C, et al. Male meiotic cytokinesis requires ceramide synthase 3-dependent sphingolipids with unique membrane anchors. Hum Mol Genet. 2015;24(17):4792–808.
Radner FP, Marrakchi S, Kirchmeier P, Kim GJ, Ribierre F, Kamoun B, et al. Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. PLoS Genet. 2013;9(6):e1003536.
Rahmann H. Functional meaning of neuronal gangliosides for the process of thermal adaptation in vertebrates. J Therm Biol. 1983;8(4):404–7.
Regier DS, Proia RL, D’Azzo A, Tifft CJ. The GM1 and GM2 gangliosidoses: natural history and progress toward therapy. Pediatr Endocrinol Rev. 2016;13(Suppl 1):663–73.
Regina Todeschini A, Hakomori SI. Functional role of glycosphingolipids and gangliosides in control of cell adhesion, motility, and growth, through glycosynaptic microdomains. Biochim Biophys Acta. 2008;1780(3):421–33.
Remmel N, Locatelli-Hoops S, Breiden B, Schwarzmann G, Sandhoff K. Saposin B mobilizes lipids from cholesterol-poor and bis(monoacylglycero)phosphate-rich membranes at acidic pH. Unglycosylated patient variant saposin B lacks lipid-extraction capacity. FEBS J. 2007;274(13):3405–20.
Riboni L, Acquotti D, Casellato R, Ghidoni R, Montagnolo G, Benevento A, et al. Changes of the human liver GM3 ganglioside molecular species during aging. Eur J Biochem. 1992;203(1-2):107–13.
Riebeling C, Allegood JC, Wang E, Merrill AH Jr, Futerman AH. Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors. J Biol Chem. 2003;278(44):43452–9.
Rieck M, Kremser C, Jobin K, Mettke E, Kurts C, Graler M, et al. Ceramide synthase 2 facilitates S1P-dependent egress of thymocytes into the circulation in mice. Eur J Immunol. 2017;47(4):677–84.
Rodrigues PS, Kale PP. Mini review – the role of Glucocerebrosidase and Progranulin as possible targets in the treatment of Parkinson’s disease. Rev Neurol (Paris). 2021;177(9):1082–9.
Rodriguez-Walker M, Daniotti JL. Human sialidase Neu3 is S-acylated and behaves like an integral membrane protein. Sci Rep. 2017;7(1):4167.
Roseman S. The synthesis of complex carbohydrates by multiglycosyltransferase systems and their potential function in intercellular adhesion. Chem Phys Lipids. 1970;5(1):270–97.
Rosenberg RN, Pascual JM. Rosenberg’s molecular and genetic basis of neurological and psychiatric disease. 6th ed. Academic Press; 2020. 1012 p
Rossmann M, Schultz-Heienbrok R, Behlke J, Remmel N, Alings C, Sandhoff K, et al. Crystal structures of human saposins C andD: implications for lipid recognition and membrane interactions. Structure. 2008;16(5):809–17.
Russo D, Della Ragione F, Rizzo R, Sugiyama E, Scalabri F, Hori K, et al. Glycosphingolipid metabolic reprogramming drives neural differentiation. EMBO J. 2018;37(7):e97674.
Saito M, Tanaka Y, Tang CP, Yu RK, Ando S. Characterization of sialidase activity in mouse synaptic plasma membranes and its age-related changes. J Neurosci Res. 1995;40(3):401–6.
Sambasivarao K, McCluer RH. Lipid components of gangliosides. J Lipid Res. 1964;5:103–8.
Sandhoff K. Bioactive glycosphingolipids with differentiation-inducing activity toward leukemia cells. Jpn J Cancer Res. 1993;84(11):inside front cover – 1339.
Sandhoff R. Very long chain sphingolipids: tissue expression, function and synthesis. FEBS Lett. 2010;584(9):1907–13.
Sandhoff K. My journey into the world of sphingolipids and sphingolipidoses. Proc Jpn Acad Ser B Phys Biol Sci. 2012;88(10):554–82.
Sandhoff K. Metabolic and cellular bases of sphingolipidoses. Biochem Soc Trans. 2013;41(6):1562–8.
Sandhoff K. Neuronal sphingolipidoses: membrane lipids and sphingolipid activator proteins regulate lysosomal sphingolipid catabolism. Biochimie. 2016;130:146–51.
Sandhoff K, Harzer K. Gangliosides and gangliosidoses: principles of molecular and metabolic pathogenesis. J Neurosci. 2013;33(25):10195–208.
Sandhoff K, Pallmann B. Membrane-bound neuraminidase from calf brain: regulation of oligosialoganglioside degradation by membrane fluidity and membrane components. Proc Natl Acad Sci U S A. 1978;75(1):122–6.
Sandhoff R, Sandhoff K. Emerging concepts of ganglioside metabolism. FEBS Lett. 2018;592(23):3835–64.
Sandhoff K, Harzer K, Wassle W, Jatzkewitz H. Enzyme alterations and lipid storage in three variants of Tay-Sachs disease. J Neurochem. 1971;18(12):2469–89.
Sandhoff R, Hepbildikler ST, Jennemann R, Geyer R, Gieselmann V, Proia RL, et al. Kidney sulfatides in mouse models of inherited glycosphingolipid disorders: determination by nano-electrospray ionization tandem mass spectrometry. J Biol Chem. 2002;277(23):20386–98.
Sandhoff R, Geyer R, Jennemann R, Paret C, Kiss E, Yamashita T, et al. Novel class of glycosphingolipids involved in male fertility. J Biol Chem. 2005;280(29):27310–8.
Sandhoff R, Schulze H, Sandhoff K. Ganglioside metabolism in health and disease. Prog Mol Biol Transl Sci. 2018;156:1–62.
Sandhoff K, Kolter T, Harzer K, Schepers U, Remmel N. Sphingolipid activator proteins. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill Education; 2019.
Sandvig K, Bergan J, Kavaliauskiene S, Skotland T. Lipid requirements for entry of protein toxins into cells. Prog Lipid Res. 2014;54:1–13.
Sango K, Yamanaka S, Hoffmann A, Okuda Y, Grinberg A, Westphal H, et al. Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism. Nat Genet. 1995;11(2):170–6.
Santha P, Dobos I, Kis G, Jancso G. Role of gangliosides in peripheral pain mechanisms. Int J Mol Sci. 2020;21(3):1005.
Sarmientos F, Schwarzmann G, Sandhoff K. Specificity of human glucosylceramide beta-glucosidase towards synthetic glucosylsphingolipids inserted into liposomes. Kinetic studies in a detergent-free assay system. Eur J Biochem. 1986;160(3):527–35.
Saroha A, Pewzner-Jung Y, Ferreira NS, Sharma P, Jouan Y, Kelly SL, et al. Critical role for very-long chain sphingolipids in invariant natural killer T cell development and homeostasis. Front Immunol. 2017;8:1386.
Saslowsky DE, te Welscher YM, Chinnapen DJ, Wagner JS, Wan J, Kern E, et al. Ganglioside GM1-mediated transcytosis of cholera toxin bypasses the retrograde pathway and depends on the structure of the ceramide domain. J Biol Chem. 2013;288(36):25804–9.
Sassa T, Hirayama T, Kihara A. Enzyme activities of the ceramide synthases CERS2-6 are regulated by phosphorylation in the C-terminal region. J Biol Chem. 2016;291(14):7477–87.
Schauer R. Sialic acids as link to Japanese scientists. Proc Jpn Acad Ser B Phys Biol Sci. 2016;92(4):109–20.
Scheel G, Acevedo E, Conzelmann E, Nehrkorn H, Sandhoff K. Model for the interaction of membrane-bound substrates and enzymes. Hydrolysis of ganglioside GD1a by sialidase of neuronal membranes isolated from calf brain. Eur J Biochem. 1982;127(2):245–53.
Scheel G, Schwarzmann G, Hoffmann-Bleihauer P, Sandhoff K. The influence of ganglioside insertion into brain membranes on the rate of ganglioside degradation by membrane-bound sialidase. Eur J Biochem. 1985;153(1):29–35.
Schengrund CL. Gangliosides: glycosphingolipids essential for normal neural development and function. Trends Biochem Sci. 2015;40(7):397–406.
Schengrund CL. Gangliosides and neuroblastomas. Int J Mol Sci. 2020;21(15):5313.
Schmidtke C, Tiede S, Thelen M, Kakela R, Jabs S, Makrypidi G, et al. Lysosomal proteome analysis reveals that CLN3-defective cells have multiple enzyme deficiencies associated with changes in intracellular trafficking. J Biol Chem. 2019;294(24):9592–604.
Schnaar RL. Gangliosides of the vertebrate nervous system. J Mol Biol. 2016;428(16):3325–36.
Schnaar RL. The biology of gangliosides. Adv Carbohydr Chem Biochem. 2019;76:113–48.
Schnabel D, Schroder M, Furst W, Klein A, Hurwitz R, Zenk T, et al. Simultaneous deficiency of sphingolipid activator proteins 1 and 2 is caused by a mutation in the initiation codon of their common gene. J Biol Chem. 1992;267(5):3312–5.
Schneider JS. Gangliosides and glycolipids in neurodegenerative disorders. Adv Neurobiol. 2014;9:449–61.
Schneider-Schaulies S, Schumacher F, Wigger D, Schol M, Waghmare T, Schlegel J, et al. Sphingolipids: effectors and achilles heals in viral infections? Cells. 2021;10(9):2175.
Schuchman EH, Desnick RJ. Niemann-Pick disease types A and B: acid sphingomyelinase deficiencies. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill Education; 2019.
Schuchman EH, McGovern MM, Desnick RJ. Niemann-Pick disease types A and B: acid sphingomyelinase deficiencies. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill Education; 2019.
Schulze H, Sandhoff K. Sphingolipids and lysosomal pathologies. Biochim Biophys Acta. 2014;1841(5):799–810.
Schwarzmann G, Hoffmann-Bleihauer P, Schubert J, Sandhoff K, Marsh D. Incorporation of ganglioside analogues into fibroblast cell membranes. A spin-label study. Biochemistry. 1983;22(21):5041–8.
Schwarzmann G, Hofmann P, Putz U, Albrecht B. Demonstration of direct glycosylation of nondegradable glucosylceramide analogs in cultured cells. J Biol Chem. 1995;270(36):21271–6.
Schwarzmann G, Breiden B, Sandhoff K. Membrane-spanning lipids for an uncompromised monitoring of membrane fusion and intermembrane lipid transfer. J Lipid Res. 2015;56(10):1861–79.
Seyfried TN, Rockwell HE, Heinecke KA, Martin DR, Sena-Esteves M. Ganglioside storage diseases: on the road to management. Adv Neurobiol. 2014;9:485–99.
Seyrantepe V, Demir SA, Timur ZK, Von Gerichten J, Marsching C, Erdemli E, et al. Murine Sialidase Neu3 facilitates GM2 degradation and bypass in mouse model of Tay-Sachs disease. Exp Neurol. 2018;299(Pt A):26–41.
Sharoar MG, Palko S, Ge Y, Saido TC, Yan R. Accumulation of saposin in dystrophic neurites is linked to impaired lysosomal functions in Alzheimer's disease brains. Mol Neurodegener. 2021;16(1):45.
Shin SH, Cho KA, Yoon HS, Kim SY, Kim HY, Pewzner-Jung Y, et al. Ceramide synthase 2 null mice are protected from ovalbumin-induced asthma with higher T cell receptor signal strength in CD4+ T cells. Int J Mol Sci. 2021;22(5):2713.
Shiozaki K, Takahashi K, Hosono M, Yamaguchi K, Hata K, Shiozaki M, et al. Phosphatidic acid-mediated activation and translocation to the cell surface of sialidase NEU3, promoting signaling for cell migration. FASEB J. 2015;29(5):2099–111.
Simons K, Gerl MJ. Revitalizing membrane rafts: new tools and insights. Nat Rev Mol Cell Biol. 2010;11(10):688–99.
Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000;1(1):31–9.
Simpson MA, Cross H, Proukakis C, Priestman DA, Neville DC, Reinkensmeier G, et al. Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet. 2004;36:1225–9.
Siow DL, Wattenberg BW. Mammalian ORMDL proteins mediate the feedback response in ceramide biosynthesis. J Biol Chem. 2012;287(48):40198–204.
Sivasubramaniyan K, Harichandan A, Schilbach K, Mack AF, Bedke J, Stenzl A, et al. Expression of stage-specific embryonic antigen-4 (SSEA-4) defines spontaneous loss of epithelial phenotype in human solid tumor cells. Glycobiology. 2015;25(8):902–17.
Smutova V, Albohy A, Pan X, Korchagina E, Miyagi T, Bovin N, et al. Structural basis for substrate specificity of mammalian neuraminidases. PLoS One. 2014;9(9):e106320.
Sociale M, Wulf AL, Breiden B, Klee K, Thielisch M, Eckardt F, et al. Ceramide synthase schlank is a transcriptional regulator adapting gene expression to energy requirements. Cell Rep. 2018;22(4):967–78.
Somogyi A, Petcherski A, Beckert B, Huebecker M, Priestman DA, Banning A, et al. Altered expression of ganglioside metabolizing enzymes results in GM3 ganglioside accumulation in cerebellar cells of a mouse model of juvenile neuronal ceroid lipofuscinosis. Int J Mol Sci. 2018;19(2):625.
Sonderfeld S, Conzelmann E, Schwarzmann G, Burg J, Hinrichs U, Sandhoff K. Incorporation and metabolism of ganglioside GM2 in skin fibroblasts from normal and GM2 gangliosidosis subjects. Eur J Biochem. 1985;149(2):247–55.
Sonnino S, Chigorno V. Ganglioside molecular species containing C18- and C20-sphingosine in mammalian nervous tissues and neuronal cell cultures. Biochim Biophys Acta. 2000;1469(2):63–77.
Sonnino S, Prinetti A. The role of sphingolipids in neuronal plasticity of the brain. J Neurochem. 2016;137(4):485–8.
Spessott W, Crespo PM, Daniotti JL, Maccioni HJ. Glycosyltransferase complexes improve glycolipid synthesis. FEBS Lett. 2012;586(16):2346–50.
Stoffel W. Sphingolipids. Annu Rev Biochem. 1971;40:57–82.
Stoffel W, LeKim D, Sticht G. Biosynthesis of dihydrosphingosine in vitro. Hoppe Seylers Z Physiol Chem. 1968a;349(5):664–70.
Stoffel W, Sticht G, LeKim D. Metabolism of sphingosine bases. IX. Degradation in vitro of dihydros**osine and dihydros**osine phosphate to palmitaldehyde and ethanolamine phosphate. Hoppe Seylers Z Physiol Chem. 1968b;349(12):1745–8.
Suzuki K. Twenty five years of the “psychosine hypothesis”: a personal perspective of its history and present status. Neurochem Res. 1998;23(3):251–9.
Suzuki K. Evolving perspective of the pathogenesis of globoid cell leukodystrophy (Krabbe disease). Proc Jpn Acad B-Phys. 2003;79(1):1–8.
Suzuki Y, Nanba E, Matsuda J, Higaki K, Oshima A. β-galactosidase deficiency (β-galactosidosis): GM1 gangliosidosis and Morquio B disease. In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill Education; 2019.
Suzuki M, Nagane M, Kato K, Yamauchi A, Shimizu T, Yamashita H, et al. Endothelial ganglioside GM3 regulates angiogenesis in solid tumors. Biochem Biophys Res Commun. 2021;569:10–6.
Svennerholm L. The chemical structure of normal human brain and Tay-Sachs gangliosides. Biochem Biophys Res Commun. 1962;9:436–41.
Svennerholm L. Designation and schematic structure of gangliosides and allied glycosphingolipids. Prog Brain Res. 1994;101:XI–XIV.
Tadano K, Ishizuka I. Isolation and partial characterization of a novel sulfoglycosphingolipid and ganglioside GM4 from rat kidney. Biochem Biophys Res Commun. 1980;97(1):126–32.
Tai T, Kotani M, Kawashima I. Differential distribution of glycosphingolipid antigens in the central nervous system. Acta Histochem Cytochem. 1999;32(3):215–22.
Takeichi T, Torrelo A, Lee JYW, Ohno Y, Lozano ML, Kihara A, et al. Biallelic mutations in KDSR disrupt ceramide synthesis and result in a spectrum of keratinization disorders associated with thrombocytopenia. J Invest Dermatol. 2017;137(11):2344–53.
Taniike M, Yamanaka S, Proia RL, Langaman C, Bone-Turrentine T, Suzuki K. Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay-Sachs disease. Acta Neuropathol. 1995;89(4):296–304.
Ternes P, Franke S, Zahringer U, Sperling P, Heinz E. Identification and characterization of a sphingolipid delta 4-desaturase family. J Biol Chem. 2002;277(28):25512–8.
Tettamanti G. Ganglioside/glycosphingolipid turnover: new concepts. Glycoconj J. 2004;20(5):301–17.
Tettamanti G, Preti A, Cestaro B, Venerando B, Lombardo A, Ghidoni R, et al. Gangliosides, neuraminidase and sialyltransferase at the nerve endings. Adv Exp Med Biol. 1980;125:263–81.
Tettamanti G, Bassi R, Viani P, Riboni L. Salvage pathways in glycosphingolipid metabolism. Biochimie. 2003;85(3-4):423–37.
Thudichum JLW. A treatise on the chemical constitution of the brain. London: Bailliere, Tindall and Cox; 1884.
Timur ZK, Akyildiz Demir S, Marsching C, Sandhoff R, Seyrantepe V. Neuraminidase-1 contributes significantly to the degradation of neuronal B-series gangliosides but not to the bypass of the catabolic block in Tay-Sachs mouse models. Mol Genet Metab Rep. 2015;4:72–82.
Tokuda N, Numata S, Li X, Nomura T, Takizawa M, Kondo Y, et al. beta4GalT6 is involved in the synthesis of lactosylceramide with less intensity than beta4GalT5. Glycobiology. 2013;23(10):1175–83.
Trinchera M, Parini R, Indellicato R, Domenighini R, dall’Olio F. Diseases of ganglioside biosynthesis: an expanding group of congenital disorders of glycosylation. Mol Genet Metab. 2018;124(4):230–7.
Turpin SM, Nicholls HT, Willmes DM, Mourier A, Brodesser S, Wunderlich CM, et al. Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab. 2014;20(4):678–86.
Valdez C, Ysselstein D, Young TJ, Zheng J, Krainc D. Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity. Hum Mol Genet. 2020;29(5):716–26.
Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. Lysosomal disorders. 2021. https://ommbid.mhmedical.com/book.aspx?bookid=2709&TopLevelContentDisplayName=Books#225069419. Accessed 2021.
van Echten G, Sandhoff K. Modulation of ganglioside biosynthesis in primary cultured neurons. J Neurochem. 1989;52(1):207–14.
Van Heyningen WE, Miller PA. The fixation of tetanus toxin by ganglioside. J Gen Microbiol. 1961;24:107–19.
van Meer G, Hoetzl S. Sphingolipid topology and the dynamic organization and function of membrane proteins. FEBS Lett. 2010;584(9):1800–5.
van Meer G, Voelker DR, Feigenson GW. Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol. 2008;9(2):112–24.
Vanier MT. Biochemical studies in Niemann-Pick disease. I. Major sphingolipids of liver and spleen. Biochim Biophys Acta. 1983;750(1):178–84.
Vanier MT. Complex lipid trafficking in Niemann-Pick disease type C. J Inherit Metab Dis. 2015;38(1):187–99.
Vanni N, Fruscione F, Ferlazzo E, Striano P, Robbiano A, Traverso M, et al. Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy. Ann Neurol. 2014;76(2):206–12.
Venkataraman K, Futerman AH. Do longevity assurance genes containing Hox domains regulate cell development via ceramide synthesis? FEBS Lett. 2002;528(1-3):3–4.
Viana GM, Priestman DA, Platt FM, Khan S, Tomatsu S, Pshezhetsky AV. Brain pathology in mucopolysaccharidoses (MPS) patients with neurological forms. J Clin Med. 2020;9(2):396.
Voelzmann A, Wulf AL, Eckardt F, Thielisch M, Brondolin M, Pesch YY, et al. Nuclear Drosophila CerS Schlank regulates lipid homeostasis via the homeodomain, independent of the lag1p motif. FEBS Lett. 2016;590(7):971–81.
Volpert G, Ben-Dor S, Tarcic O, Duan J, Saada A, Merrill AH Jr, et al. Oxidative stress elicited by modifying the ceramide acyl chain length reduces the rate of clathrin-mediated endocytosis. J Cell Sci. 2017;130(8):1486–93.
Wang F, Dai YX, Zhu XF, Chen QL, Zhu HH, Zhou B, et al. Saturated very long chain fatty acid configures glycosphingolipid for lysosome homeostasis in long-lived C. elegans. Nat Commun. 2021a;12(1):1–4.
Wang J, Zhang Q, Lu Y, Dong Y, Dhandapani KM, Brann DW, et al. Ganglioside GD3 is up-regulated in microglia and regulates phagocytosis following global cerebral ischemia. J Neurochem. 2021b;158(3):737–52.
Wang XM, Zeng P, Fang YY, Zhang T, Tian Q. Progranulin in neurodegenerative dementia. J Neurochem. 2021c;158(2):119–37.
Watanabe S, Endo S, Oshima E, Hoshi T, Higashi H, Yamada K, et al. Glycosphingolipid synthesis in cerebellar Purkinje neurons: roles in myelin formation and axonal homeostasis. Glia. 2010;58(10):1197–207.
Wegner MS, Schiffmann S, Parnham MJ, Geisslinger G, Grosch S. The enigma of ceramide synthase regulation in mammalian cells. Prog Lipid Res. 2016;63:93–119.
Wendeler M, Werth N, Maier T, Schwarzmann G, Kolter T, Schoeniger M, et al. The enzyme-binding region of human GM2-activator protein. FEBS J. 2006;273(5):982–91.
Wenger DA, Escolar ML, Luzi P, Rafi MA. Krabbe disease (globoid cell leukodystrophy). In: Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. The online metabolic and molecular bases of inherited disease. New York: McGraw-Hill Education; 2019.
Werth N, Schuette CG, Wilkening G, Lemm T, Sandhoff K. Degradation of membrane-bound ganglioside GM2 by beta -hexosaminidase A. Stimulation by GM2 activator protein and lysosomal lipids. J Biol Chem. 2001;276(16):12685–90.
Wiegandt H. The chemical constitution of gangliosides of the vertebrate nervous system. Behav Brain Res. 1995;66(1-2):85–97.
Wikipedia. 2021. https://en.wikipedia.org/wiki/Granulin. Accessed 2021.
Wilkening G, Linke T, Sandhoff K. Lysosomal degradation on vesicular membrane surfaces. Enhanced glucosylceramide degradation by lysosomal anionic lipids and activators. J Biol Chem. 1998;273(46):30271–8.
Wilkening G, Linke T, Uhlhorn-Dierks G, Sandhoff K. Degradation of membrane-bound ganglioside GM1. Stimulation by bis(monoacylglycero)phosphate and the activator proteins SAP-B And GM2- AP. J Biol Chem. 2000;275(46):35814–9.
Williams RD, Wang E, Merrill AH Jr. Enzymology of long-chain base synthesis by liver: characterization of serine palmitoyltransferase in rat liver microsomes. Arch Biochem Biophys. 1984;228(1):282–91.
Wollert T, Hurley JH. Molecular mechanism of multivesicular body biogenesis by ESCRT complexes. Nature. 2010;464(7290):864–9.
Wu G, Lu ZH, Kulkarni N, Amin R, Ledeen RW. Mice lacking major brain gangliosides develop parkinsonism. Neurochem Res. 2011;36(9):1706–14.
Wu G, Lu ZH, Seo JH, Alselehdar SK, DeFrees S, Ledeen RW. Mice deficient in GM1 manifest both motor and non-motor symptoms of Parkinson's disease; successful treatment with synthetic GM1 ganglioside. Exp Neurol. 2020;329:113284.
Yamaji T, Hanada K. Sphingolipid metabolism and interorganellar transport: localization of sphingolipid enzymes and lipid transfer proteins. Traffic. 2015;16(2):101–22.
Yamakawa T. Studies on erythrocyte glycolipids. Proc Jpn Acad Ser B. 2005;81(B):52–63.
Yamakawa T, Nagai Y. Glycolipids at the cell surface and their biological functions. Trends Biochem Sci. 1978;3(2):128–31.
Yamashita T, Wada R, Sasaki T, Deng C, Bierfreund U, Sandhoff K, et al. A vital role for glycosphingolipid synthesis during development and differentiation. Proc Natl Acad Sci U S A. 1999;96(16):9142–7.
Yang LJ, Zeller CB, Shaper NL, Kiso M, Hasegawa A, Shapiro RE, et al. Gangliosides are neuronal ligands for myelin-associated glycoprotein. Proc Natl Acad Sci U S A. 1996;93(2):814–8.
Yanguas-Casas N, Ojalvo-Sanz AC, Martinez-Vazquez A, Goneau MF, Gilbert M, Nieto-Sampedro M, et al. Neurostatin and other O-acetylated gangliosides show anti-neuroinflammatory activity involving the NF kappa B pathway. Toxicol Appl Pharm. 2019;377:114627.
Yates AJ. Gangliosides in the nervous system during development and regeneration. Neurochem Pathol. 1986;5(3):309–29.
Yoneshige A, Sasaki A, Miyazaki M, Kojima N, Suzuki A, Matsuda J. Developmental changes in glycolipids and synchronized expression of nutrient transporters in the mouse small intestine. J Nutr Biochem. 2010;21(3):214–26.
Yoo SW, Motari MG, Susuki K, Prendergast J, Mountney A, Hurtado A, et al. Sialylation regulates brain structure and function. FASEB J. 2015;29(7):3040–53.
Yoshida Y, Kojima N, Kurosawa N, Hamamoto T, Tsuji S. Molecular cloning of Sia alpha 2,3Gal beta 1,4GlcNAc alpha 2,8-sialyltransferase from mouse brain. J Biol Chem. 1995;270(24):14628–33.
Yoshikawa M, Go S, Takasaki K, Kakazu Y, Ohashi M, Nagafuku M, et al. Mice lacking ganglioside GM3 synthase exhibit complete hearing loss due to selective degeneration of the organ of Corti. Proc Natl Acad Sci U S A. 2009;106(23):9483–8.
Yoshikawa M, Go S, Suzuki S, Suzuki A, Katori Y, Morlet T, et al. Ganglioside GM3 is essential for the structural integrity and function of cochlear hair cells. Hum Mol Genet. 2015;24(10):2796–807.
Yu RK, Itokazu Y. Glycolipid and glycoprotein expression during neural development. Adv Neurobiol. 2014;9:185–222.
Yu RK, Bieberich E, **a T, Zeng G. Regulation of ganglioside biosynthesis in the nervous system. J Lipid Res. 2004;45(5):783–93.
Yusuf HK, Pohlentz G, Sandhoff K. Tunicamycin inhibits ganglioside biosynthesis in rat liver Golgi apparatus by blocking sugar nucleotide transport across the membrane vesicles. Proc Natl Acad Sci U S A. 1983a;80(23):7075–9.
Yusuf HK, Pohlentz G, Schwarzmann G, Sandhoff K. Ganglioside biosynthesis in Golgi apparatus of rat liver. Stimulation by phosphatidylglycerol and inhibition by tunicamycin. Eur J Biochem. 1983b;134(1):47–54.
Yusuf HK, Pohlentz G, Sandhoff K. Ganglioside biosynthesis in Golgi apparatus: new perspectives on its mechanism. J Neurosci Res. 1984;12(2-3):161–78.
Zhao L, Spassieva SD, Jucius TJ, Shultz LD, Shick HE, Macklin WB, et al. A deficiency of ceramide biosynthesis causes cerebellar purkinje cell neurodegeneration and lipofuscin accumulation. PLoS Genet. 2011;7(5):e1002063.
Zhao L, Spassieva S, Gable K, Gupta SD, Shi LY, Wang J, et al. Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration. Proc Natl Acad Sci U S A. 2015;112(42):12962–7.
Zigdon H, Kogot-Levin A, Park JW, Goldschmidt R, Kelly S, Merrill AH Jr, et al. Ablation of ceramide synthase 2 causes chronic oxidative stress due to disruption of the mitochondrial respiratory chain. J Biol Chem. 2013;288(7):4947–56.
Acknowledgement
The work of the authors was supported by grants of the DFG (German Research Association). We thank Christina Schuette (ProSciencia, Lübeck) for helpful corrections and discussions and Bernadette Breiden for her support on the graphical work. We also thank the very helpful library service at the German Cancer Research Center in retrieving all the literature.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Sandhoff, R., Sandhoff, K. (2023). Neuronal Ganglioside and Glycosphingolipid (GSL) Metabolism and Disease. In: Schengrund, CL., Yu, R.K. (eds) Glycobiology of the Nervous System. Advances in Neurobiology, vol 29. Springer, Cham. https://doi.org/10.1007/978-3-031-12390-0_12
Download citation
DOI: https://doi.org/10.1007/978-3-031-12390-0_12
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-12389-4
Online ISBN: 978-3-031-12390-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)