Gangliosides pp 97-141 | Cite as

Ganglioside Metabolism and Its Inherited Diseases

  • Bernadette Breiden
  • Konrad SandhoffEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1804)


Gangliosides are sialic acid containing glycosphingolipids, which are abundant in mammalian brain tissue. Several fatal human diseases are caused by defects in glycolipid metabolism. Defects in their degradation lead to an accumulation of metabolites upstream of the defective reactions, whereas defects in their biosynthesis lead to diverse problems in a large number of organs.

Gangliosides are primarily positioned with their ceramide anchor in the neuronal plasma membrane and the glycan head group exposed on the cell surface. Their biosynthesis starts in the endoplasmic reticulum with the formation of the ceramide anchor, followed by sequential glycosylation reactions, mainly at the luminal surface of Golgi and TGN membranes, a combinatorial process, which is catalyzed by often promiscuous membrane-bound glycosyltransferases.

Thereafter, the gangliosides are transported to the plasma membrane by exocytotic membrane flow. After endocytosis, they are degraded within the endolysosomal compartments by a complex machinery of degrading enzymes, lipid-binding activator proteins, and negatively charged lipids.


Glycosphingolipids Biosynthesis Catabolism Bis(monoacylglycero)phosphate Sialic acid Membranes Luminal vesicles Ceramide Gangliosidosis 



We thank Roger Sandhoff and Christina Schuette for helpful corrections and discussions. This work was supported by German Research Foundation Grants SFB 645 and TRR83.


  1. 1.
    Thudichum JLW (1884) A treatise on the chemical constitution of the brain. London, Bailliere, Tindall and CoxGoogle Scholar
  2. 2.
    Klenk E (1939) Niemann-Pick’sche Krankheit und Amaurotische Idiotie. Hoppe-Seyler’s Z Physiol Chem 262:128–143CrossRefGoogle Scholar
  3. 3.
    Klenk E (1942) Über die Ganglioside, eine neue Gruppe von zuckerhaltigen Gehirnlipoiden. Hoppe Seyler’s Z Physiol Chem 273:76–86CrossRefGoogle Scholar
  4. 4.
    Kuhn R, Wiegandt H (1963) Die Konstitution der Ganglio-N-tetraose und des Gangliosids GI. Chem Ber 96:866–880CrossRefGoogle Scholar
  5. 5.
    Jatzkewitz H, Sandhoff K (1963) On a biochemically special form of infantile amaurotic idiocy. Biochim Biophys Acta 70:354–356CrossRefPubMedGoogle Scholar
  6. 6.
    Sandhoff K, Harzer K, Wässle W, Jatzkewitz H (1971) Enzyme alterations and lipid storage in three variants of Tay-Sachs disease. J Neurochem 18(12):2469–2489CrossRefPubMedGoogle Scholar
  7. 7.
    Harzer K, Jatzkewitz H, Sandhoff K (1969) Incorporation of labelled glucose into the individual major gangliosides of the brain of young rats. J Neurochem 16(8):1279–1282CrossRefPubMedGoogle Scholar
  8. 8.
    Skotland T, Ekroos K, Kavaliauskiene S, Bergan J, Kauhanen D, Lintonen T, Sandvig K (2016) Determining the turnover of glycosphingolipid species by stable-isotope tracer lipidomics. J Mol Biol 428(24 Pt A):4856–4866. CrossRefPubMedGoogle Scholar
  9. 9.
    Aureli M, Samarani M, Murdica V, Mauri L, Loberto N, Bassi R, Prinetti A, Sonnino S (2014) Gangliosides and cell surface ganglioside glycohydrolases in the nervous system. Adv Neurobiol 9:223–244. CrossRefPubMedGoogle Scholar
  10. 10.
    Aureli M, Loberto N, Lanteri P, Chigorno V, Prinetti A, Sonnino S (2011) Cell surface sphingolipid glycohydrolases in neuronal differentiation and aging in culture. J Neurochem 116(5):891–899. CrossRefPubMedGoogle Scholar
  11. 11.
    Sandhoff K (2012) My journey into the world of sphingolipids and sphingolipidoses. Proc Jpn Acad Ser B 88:554–582CrossRefGoogle Scholar
  12. 12.
    Mehl E, Jatzkewitz H (1964) Eine cerebrosidsulfatase aus Schweineniere. Hoppe-Seylers. Zeitschr Physiol Chem 339(1–6):260–276CrossRefGoogle Scholar
  13. 13.
    Conzelmann E, Sandhoff K (1978) 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 75(8):3979–3983PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Yamakawa T (1996) A reflection on the early history of glycosphingolipids. Glycoconj J 13(2):123–126. CrossRefPubMedGoogle Scholar
  15. 15.
    Wiegandt H (1968) The structure and the function of gangliosides. Angew Chem Int Ed Engl 7(2):87–96. CrossRefPubMedGoogle Scholar
  16. 16.
    Wiegandt H (1995) The chemical constitution of gangliosides of the vertebrate nervous system. Behav Brain Res 66(1–2):85–97CrossRefPubMedGoogle Scholar
  17. 17.
    Sandhoff R, Geyer R, Jennemann R, Paret C, Kiss E, Yamashita T, Gorgas K, Sijmonsma TP, Iwamori M, Finaz C, Proia RL, Wiegandt H, Gröne HJ (2005) Novel class of glycosphingolipids involved in male fertility. J Biol Chem 280(29):27310–27318. CrossRefPubMedGoogle Scholar
  18. 18.
    Posse de Chaves E, Sipione S (2010) Sphingolipids and gangliosides of the nervous system in membrane function and dysfunction. FEBS Lett 584(9):1748–1759. CrossRefPubMedGoogle Scholar
  19. 19.
    Jennemann R, Sandhoff R, Wang S, Kiss E, Gretz N, Zuliani C, Martin-Villalba A, Jäger R, Schorle H, Kenzelmann M, Bonrouhi M, Wiegandt H, Gröne H-J (2005) Cell-specific deletion of glucosylceramide synthase in brain leads to severe neural defects after birth. Proc Natl Acad Sci U S A 102(35):12459–12464PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Yamashita T, Wu YP, Sandhoff R, Werth N, Mizukami H, Ellis JM, Dupree JL, Geyer R, Sandhoff K, Proia RL (2005) Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon-glial interactions. Proc Natl Acad Sci U S A 102(8):2725–2730PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Fukushi Y, Hakomori S, Shepard T (1984) Localization and alteration of mono-, di-, and trifucosyl alpha 1–3 type 2 chain structures during human embryogenesis and in human cancer. J Exp Med 160(2):506–520CrossRefPubMedGoogle Scholar
  22. 22.
    Ichikawa S, Nakajo N, Sakiyama H, Hirabayashi Y (1994) A mouse B16 melanoma mutant deficient in glycolipids. Proc Natl Acad Sci U S A 91(7):2703–2707PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Kolter T, Magin TM, Sandhoff K (2000) Biomolecule function: no reliable prediction from cell culture. Traffic 1(10):803–804CrossRefPubMedGoogle Scholar
  24. 24.
    Schnaar RL (2010) Brain gangliosides in axon-myelin stability and axon regeneration. FEBS Lett 584(9):1741–1747. CrossRefPubMedGoogle Scholar
  25. 25.
    Merrill AH Jr (2002) De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J Biol Chem 277(29):25843–25846. CrossRefPubMedGoogle Scholar
  26. 26.
    Merrill AH Jr (2011) Sphingolipid and glycosphingolipid metabolic pathways in the era of sphingolipidomics. Chem Rev 111(10):6387–6422. CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Rother J, van Echten G, Schwarzmann G, Sandhoff K (1992) Biosynthesis of sphingolipids: dihydroceramide and not sphinganine is desaturated by cultured cells. Biochem Biophys Res Commun 189(1):14–20CrossRefPubMedGoogle Scholar
  28. 28.
    Michel C, van Echten-Deckert G, Rother J, Sandhoff K, Wang E, Merrill AH Jr (1997) Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide. J Biol Chem 272(36):22432–22437CrossRefPubMedGoogle Scholar
  29. 29.
    Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, Narra K, Hoehn KL, Knotts TA, Siesky A, Nelson DH, Karathanasis SK, Fontenot GK, Birnbaum MJ, Summers SA (2007) Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5(3):167–179. CrossRefPubMedGoogle Scholar
  30. 30.
    Hanada K (2003) Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. Biochim Biophys Acta 1632(1–3):16–30CrossRefPubMedGoogle Scholar
  31. 31.
    Sonnino S, Chigorno V (2000) Ganglioside molecular species containing C18- and C20-sphingosine in mammalian nervous tissues and neuronal cell cultures. Biochim Biophys Acta 1469(2):63–77CrossRefPubMedGoogle Scholar
  32. 32.
    Palestini P, Masserini M, Sonnino S, Giuliani A, Tettamanti G (1990) Changes in the ceramide composition of rat forebrain gangliosides with age. J Neurochem 54(1):230–235CrossRefPubMedGoogle Scholar
  33. 33.
    Zhao L, Spassieva S, Gable K, Gupta SD, Shi LY, Wang J, Bielawski J, Hicks WL, Krebs MP, Naggert J, Hannun YA, Dunn TM, Nishina PM (2015) 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 112(42):12962–12967. CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Davidson G, Murphy S, Polke J, Laura M, Salih M, Muntoni F, Blake J, Brandner S, Davies N, Horvath R, Price S, Donaghy M, Roberts M, Foulds N, Ramdharry G, Soler D, Lunn M, Manji H, Davis M, Houlden H, Reilly M (2012) Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. Journal of neurology 259(8):1673–1685. CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Astudillo L, Sabourdy F, Therville N, Bode H, Segui B, Andrieu-Abadie N, Hornemann T, Levade T (2015) Human genetic disorders of sphingolipid biosynthesis. J Inherit Metab Dis 38(1):65–76. CrossRefPubMedGoogle Scholar
  36. 36.
    Penno A, Reilly MM, Houlden H, Laura M, Rentsch K, Niederkofler V, Stoeckli ET, Nicholson G, Eichler F, Brown RH Jr, von Eckardstein A, Hornemann T (2010) Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem 285(15):11178–11187. CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Zitomer NC, Mitchell T, Voss KA, Bondy GS, Pruett ST, Garnier-Amblard EC, Liebeskind LS, Park H, Wang E, Sullards MC, Merrill AH Jr, Riley RT (2009) Ceramide synthase inhibition by fumonisin B1 causes accumulation of 1-deoxysphinganine: a novel category of bioactive 1-deoxysphingoid bases and 1-deoxydihydroceramides biosynthesized by mammalian cell lines and animals. J Biol Chem 284(8):4786–4795. CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Garofalo K, Penno A, Schmidt BP, Lee HJ, Frosch MP, von Eckardstein A, Brown RH, Hornemann T, Eichler FS (2011) Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest 121(12):4735–4745. CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Alecu I, Othman A, Penno A, Saied EM, Arenz C, von Eckardstein A, Hornemann T (2017) Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway. J Lipid Res 58(1):60–71. CrossRefPubMedGoogle Scholar
  40. 40.
    Mullen TD, Hannun YA, Obeid LM (2012) Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochem J 441(3):789–802. CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Grosch S, Schiffmann S, Geisslinger G (2012) Chain length-specific properties of ceramides. Prog Lipid Res 51(1):50–62. CrossRefPubMedGoogle Scholar
  42. 42.
    Sassa T, Hirayama T, Kihara A (2016) Enzyme activities of the ceramide synthases CERS2-6 are regulated by phosphorylation in the C-terminal region. J Biol Chem 291(14):7477–7487. CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Yu RK, Bieberich E, Xia T, Zeng G (2004) Regulation of ganglioside biosynthesis in the nervous system. J Lipid Res 45(5):783–793. CrossRefPubMedGoogle Scholar
  44. 44.
    Wegner MS, Schiffmann S, Parnham MJ, Geisslinger G, Grosch S (2016) The enigma of ceramide synthase regulation in mammalian cells. Prog Lipid Res 63:93–119. CrossRefPubMedGoogle Scholar
  45. 45.
    Mullen TD, Spassieva S, Jenkins RW, Kitatani K, Bielawski J, Hannun YA, Obeid LM (2011) Selective knockdown of ceramide synthases reveals complex interregulation of sphingolipid metabolism. J Lipid Res 52(1):68–77. CrossRefPubMedCentralPubMedGoogle Scholar
  46. 46.
    Mosbech MB, Olsen AS, Neess D, Ben-David O, Klitten LL, Larsen J, Sabers A, Vissing J, Nielsen JE, Hasholt L, Klein AD, Tsoory MM, Hjalgrim H, Tommerup N, Futerman AH, Mοller RS, Fӕrgeman NJ (2014) Reduced ceramide synthase 2 activity causes progressive myoclonic epilepsy. Ann Clin Trans Neurol 1(2):88–98. CrossRefGoogle Scholar
  47. 47.
    Ebel P, Vom Dorp K, Petrasch-Parwez E, Zlomuzica A, Kinugawa K, Mariani J, Minich D, Ginkel C, Welcker J, Degen J, Eckhardt M, Dere E, Dörmann P, Willecke K (2013) Inactivation of ceramide synthase 6 in mice results in an altered sphingolipid metabolism and behavioral abnormalities. J Biol Chem 288(29):21433–21447. CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.
    Turpin SM, Nicholls HT, Willmes DM, Mourier A, Brodesser S, Wunderlich CM, Mauer J, Xu E, Hammerschmidt P, Brönneke HS, Trifunovic A, LoSasso G, Wunderlich FT, Kornfeld JW, Blüher M, Krönke M, Brüning JC (2014) Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab 20(4):678–686. CrossRefPubMedGoogle Scholar
  49. 49.
    Ginkel C, Hartmann D, vom Dorp K, Zlomuzica A, Farwanah H, Eckhardt M, Sandhoff R, Degen J, Rabionet M, Dere E, Dörmann P, Sandhoff K, Willecke K (2012) Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelin-associated glycoprotein in oligodendrocytes. J Biol Chem 287(50):41888–41902. CrossRefPubMedCentralPubMedGoogle Scholar
  50. 50.
    Zhao L, Spassieva SD, Jucius TJ, Shultz LD, Shick HE, Macklin WB, Hannun YA, Obeid LM, Ackerman SL (2011) A deficiency of ceramide biosynthesis causes cerebellar purkinje cell neurodegeneration and lipofuscin accumulation. PLoS Genet 7(5):e1002063. CrossRefPubMedCentralPubMedGoogle Scholar
  51. 51.
    Spassieva SD, Ji X, Liu Y, Gable K, Bielawski J, Dunn TM, Bieberich E, Zhao L (2016) Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency. Proc Natl Acad Sci U S A 113(21):5928–5933. CrossRefPubMedCentralPubMedGoogle Scholar
  52. 52.
    Gosejacob D, Jäger PS, Vom Dorp K, Frejno M, Carstensen AC, Köhnke M, Degen J, Dörmann P, Hoch M (2016) Ceramide synthase 5 is essential to maintain C16:0-ceramide pools and contributes to the development of diet-induced obesity. J Biol Chem 291(13):6989–7003. CrossRefPubMedCentralPubMedGoogle Scholar
  53. 53.
    Jennemann R, Rabionet M, Gorgas K, Epstein S, Dalpke A, Rothermel U, Bayerle A, van der Hoeven F, Imgrund S, Kirsch J, Nickel W, Willecke K, Riezman H, Gröne HJ, Sandhoff R (2012) Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum Mol Genet 21(3):586–608. CrossRefPubMedGoogle Scholar
  54. 54.
    Rabionet M, Bayerle A, Jennemann R, Heid H, Fuchser J, Marsching C, Porubsky S, Bolenz C, Guillou F, Grone HJ, Gorgas K, Sandhoff R (2015) Male meiotic cytokinesis requires ceramide synthase 3-dependent sphingolipids with unique membrane anchors. Hum Mol Genet 24(17):4792–4808. CrossRefPubMedGoogle Scholar
  55. 55.
    Eckl KM, Tidhar R, Thiele H, Oji V, Hausser I, Brodesser S, Preil ML, Onal-Akan A, Stock F, Müller D, Becker K, Casper R, Nürnberg G, Altmüller J, Nürnberg P, Traupe H, Futerman AH, Hennies HC (2013) Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length. J Invest Dermatol 133(9):2202–2211. CrossRefPubMedGoogle Scholar
  56. 56.
    Radner FP, Marrakchi S, Kirchmeier P, Kim GJ, Ribierre F, Kamoun B, Abid L, Leipoldt M, Turki H, Schempp W, Heilig R, Lathrop M, Fischer J (2013) Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. PLoS Genet 9(6):e1003536. CrossRefPubMedCentralPubMedGoogle Scholar
  57. 57.
    Imgrund S, Hartmann D, Farwanah H, Eckhardt M, Sandhoff R, Degen J, Gieselmann V, Sandhoff K, Willecke K (2009) Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. J Biol Chem 284(48):33549–33560PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Pewzner-Jung Y, Brenner O, Braun S, Laviad EL, Ben-Dor S, Feldmesser E, Horn-Saban S, Amann-Zalcenstein D, Raanan C, Berkutzki T, Erez-Roman R, Ben-David O, Levy M, Holzman D, Park H, Nyska A, Merrill AH Jr, Futerman AH (2010) A critical role for ceramide synthase 2 in liver homeostasis: II. insights into molecular changes leading to hepatopathy. J Biol Chem 285(14):10911–10923. CrossRefPubMedCentralPubMedGoogle Scholar
  59. 59.
    Pewzner-Jung Y, Park H, Laviad EL, Silva LC, Lahiri S, Stiban J, Erez-Roman R, Brügger B, Sachsenheimer T, Wieland F, Prieto M, Merrill AH Jr, Futerman AH (2010) A critical role for ceramide synthase 2 in liver homeostasis: I. Alterations in lipid metabolic pathways. J Biol Chem 285(14):10902–10910. CrossRefPubMedCentralPubMedGoogle Scholar
  60. 60.
    Silva LC, Ben David O, Pewzner-Jung Y, Laviad EL, Stiban J, Bandyopadhyay S, Merrill AH Jr, Prieto M, Futerman AH (2012) Ablation of ceramide synthase 2 strongly affects biophysical properties of membranes. J Lipid Res 53(3):430–436. CrossRefPubMedCentralPubMedGoogle Scholar
  61. 61.
    Zigdon H, Kogot-Levin A, Park JW, Goldschmidt R, Kelly S, Merrill AH Jr, Scherz A, Pewzner-Jung Y, Saada A, Futerman AH (2013) Ablation of ceramide synthase 2 causes chronic oxidative stress due to disruption of the mitochondrial respiratory chain. J Biol Chem 288(7):4947–4956. CrossRefPubMedCentralPubMedGoogle Scholar
  62. 62.
    Ben-David O, Pewzner-Jung Y, Brenner O, Laviad EL, Kogot-Levin A, Weissberg I, Biton IE, Pienik R, Wang E, Kelly S, Alroy J, Raas-Rothschild A, Friedman A, Brugger B, Merrill AH Jr, Futerman AH (2011) Encephalopathy caused by ablation of very long acyl chain ceramide synthesis may be largely due to reduced galactosylceramide levels. J Biol Chem 286(34):30022–30033. CrossRefPubMedCentralPubMedGoogle Scholar
  63. 63.
    Park WJ, Brenner O, Kogot-Levin A, Saada A, Merrill AH Jr, Pewzner-Jung Y, Futerman AH (2015) Development of pheochromocytoma in ceramide synthase 2 null mice. Endocr Relat Cancer 22(4):623–632. CrossRefPubMedCentralPubMedGoogle Scholar
  64. 64.
    Ledeen RW, Yu RK, Eng LF (1973) Gangliosides of human myelin: sialosylgalactosylceramide (G7) as a major component. J Neurochem 21(4):829–839CrossRefPubMedGoogle Scholar
  65. 65.
    Mullin BR, Patrick DH, Poore CM, Smith MT (1984) Prevention of experimental allergic encephalomyelitis by ganglioside GM4. Brain Res 296(1):174–176CrossRefPubMedGoogle Scholar
  66. 66.
    Coste H, Martel MB, Got R (1986) Topology of glucosylceramide synthesis in Golgi membranes from porcine submaxillary glands. Biochim Biophys Acta 858(1):6–12CrossRefPubMedGoogle Scholar
  67. 67.
    Jeckel D, Karrenbauer A, Burger KN, van Meer G, Wieland F (1992) Glucosylceramide is synthesized at the cytosolic surface of various Golgi subfractions. J Cell Biol 117(2):259–267CrossRefPubMedGoogle Scholar
  68. 68.
    Ichikawa S, Sakiyama H, Suzuki G, Hidari KI, Hirabayashi Y (1996) Expression cloning of a cDNA for human ceramide glucosyltransferase that catalyzes the first glycosylation step of glycosphingolipid synthesis. Proc Natl Acad Sci U S A 93(10):4638–4643PubMedCentralCrossRefPubMedGoogle Scholar
  69. 69.
    Futerman AH, Pagano RE (1991) Determination of the intracellular sites and topology of glucosylceramide synthesis in rat liver. Biochem J 280(2):295–302PubMedCentralCrossRefPubMedGoogle Scholar
  70. 70.
    Marks DL, Wu K, Paul P, Kamisaka Y, Watanabe R, Pagano RE (1999) Oligomerization and topology of the Golgi membrane protein glucosylceramide synthase. J Biol Chem 274(1):451–456CrossRefPubMedGoogle Scholar
  71. 71.
    D'Angelo G, Uemura T, Chuang CC, Polishchuk E, Santoro M, Ohvo-Rekila H, Sato T, Di Tullio G, Varriale A, D'Auria S, Daniele T, Capuani F, Johannes L, Mattjus P, Monti M, Pucci P, Williams RL, Burke JE, Platt FM, Harada A, De Matteis MA (2013) Vesicular and non-vesicular transport feed distinct glycosylation pathways in the Golgi. Nature 501(7465):116–120. CrossRefPubMedGoogle Scholar
  72. 72.
    De Matteis MA, Di Campli A, D'Angelo G (2007) Lipid-transfer proteins in membrane trafficking at the Golgi complex. Biochim Biophys Acta 1771(6):761–768. CrossRefPubMedGoogle Scholar
  73. 73.
    Hanada K, Kumagai K, Yasuda S, Miura Y, Kawano M, Fukasawa M, Nishijima M (2003) Molecular machinery for non-vesicular trafficking of ceramide. Nature 426(6968):803–809. CrossRefPubMedGoogle Scholar
  74. 74.
    Lannert H, Bünning C, Jeckel D, Wieland FT (1994) Lactosylceramide is synthesized in the lumen of the Golgi apparatus. FEBS Lett 342(1):91–96CrossRefPubMedGoogle Scholar
  75. 75.
    Buton X, Hervé P, Kubelt J, Tannert A, Burger KN, Fellmann P, Müller P, Herrmann A, Seigneuret M, Devaux PF (2002) Transbilayer movement of monohexosylsphingolipids in endoplasmic reticulum and Golgi membranes. Biochemistry 41(43):13106–13115CrossRefPubMedGoogle Scholar
  76. 76.
    Eckford PD, Sharom FJ (2005) The reconstituted P-glycoprotein multidrug transporter is a flippase for glucosylceramide and other simple glycosphingolipids. Biochem J 389(Pt 2):517–526. CrossRefPubMedCentralPubMedGoogle Scholar
  77. 77.
    Lannert H, Gorgas K, Meissner I, Wieland FT, Jeckel D (1998) Functional organization of the Golgi apparatus in glycosphingolipid biosynthesis. Lactosylceramide and subsequent glycosphingolipids are formed in the lumen of the late Golgi. J Biol Chem 273(5):2939–2946CrossRefPubMedGoogle Scholar
  78. 78.
    Tokuda N, Numata S, Li X, Nomura T, Takizawa M, Kondo Y, Yamashita Y, Hashimoto N, Kiyono T, Urano T, Furukawa K, Furukawa K (2013) Beta4GalT6 is involved in the synthesis of lactosylceramide with less intensity than beta4GalT5. Glycobiology 23(10):1175–1183. CrossRefPubMedGoogle Scholar
  79. 79.
    D'Angelo G, Polishchuk E, Di Tullio G, Santoro M, Di Campli A, Godi A, West G, Bielawski J, Chuang CC, van der Spoel AC, Platt FM, Hannun YA, Polishchuk R, Mattjus P, De Matteis MA (2007) Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature 449(7158):62–67CrossRefPubMedGoogle Scholar
  80. 80.
    Roseman S (1970) The synthesis of complex carbohydrates by multiglycosyltransferase systems and their potential function in intercellular adhesion. Chem Phys Lipids 5(1):270–297CrossRefPubMedGoogle Scholar
  81. 81.
    Yusuf HK, Pohlentz G, Schwarzmann G, Sandhoff K (1983) Ganglioside biosynthesis in Golgi apparatus of rat liver. Stimulation by phosphatidylglycerol and inhibition by tunicamycin. Eur J Biochem 134(1):47–54CrossRefPubMedGoogle Scholar
  82. 82.
    Yusuf HK, Pohlentz G, Sandhoff K (1984) Ganglioside biosynthesis in Golgi apparatus: new perspectives on its mechanism. J Neurosci Res 12(2–3):161–178CrossRefPubMedGoogle Scholar
  83. 83.
    Simons K, Gerl MJ (2010) Revitalizing membrane rafts: new tools and insights. Nat Rev Mol Cell Biol 11(10):688–699. CrossRefPubMedGoogle Scholar
  84. 84.
    Simons K, Toomre D (2000) Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1(1):31–39. CrossRefGoogle Scholar
  85. 85.
    Bagatolli LA, Gratton E (2000) Two photon fluorescence microscopy of coexisting lipid domains in giant unilamellar vesicles of binary phospholipid mixtures. Biophys J 78(1):290–305. CrossRefPubMedCentralPubMedGoogle Scholar
  86. 86.
    Baumgart T, Hess ST, Webb WW (2003) Imaging coexisting fluid domains in biomembrane models coupling curvature and line tension. Nature 425(6960):821–824. CrossRefPubMedGoogle Scholar
  87. 87.
    Mukherjee S, Maxfield FR (2000) Role of membrane organization and membrane domains in endocytic lipid trafficking. Traffic 1(3):203–211CrossRefPubMedGoogle Scholar
  88. 88.
    Spessott W, Crespo PM, Daniotti JL, Maccioni HJ (2012) Glycosyltransferase complexes improve glycolipid synthesis. FEBS Lett 586(16):2346–2350. CrossRefPubMedGoogle Scholar
  89. 89.
    Keenan TW, Morre DJ, Basu S (1974) Ganglioside biosynthesis. Concentration of glycosphingolipid glycosyltransferases in Golgi apparatus from rat liver. J Biol Chem 249(1):310–315PubMedGoogle Scholar
  90. 90.
    Kaufman B, Basu S, Roseman S (1968) Enzymatic synthesis of disialogangliosides from monosialogangliosides by sialyltransferases from embryonic chicken brain. J Biol Chem 243(21):5804–5807PubMedGoogle Scholar
  91. 91.
    Pohlentz G, Klein D, Schmitz D, Schwarzmann G, Peter-Katalinic J, Sandhoff K (1988) Biosynthesis of gangliosides from asialogangliosides in rat liver Golgi vesicles. Biol Chem Hoppe Seyler 369(1):55–63CrossRefPubMedGoogle Scholar
  92. 92.
    Pohlentz G, Klein D, Schwarzmann G, Schmitz D, Sandhoff K (1988) 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 85(19):7044–7048PubMedCentralCrossRefPubMedGoogle Scholar
  93. 93.
    Iber H, Zacharias C, Sandhoff K (1992) 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 2(2):137–142CrossRefPubMedGoogle Scholar
  94. 94.
    Iber H, Sandhoff K (1989) Identity of GD1C, GT1a and GQ1b synthase in Golgi vesicles from rat liver. FEBS Lett 254(1–2):124–128CrossRefPubMedGoogle Scholar
  95. 95.
    Iber H, van Echten G, Sandhoff K (1991) Substrate specificity of alpha 2–3-sialyltransferases in ganglioside biosynthesis of rat liver golgi. Eur J Biochem 195(1):115–120CrossRefPubMedGoogle Scholar
  96. 96.
    Iber H, van Echten G, Sandhoff K (1992) Fractionation of primary cultured cerebellar neurons: distribution of sialyltransferases involved in ganglioside biosynthesis. J Neurochem 58(4):1533–1537CrossRefPubMedGoogle Scholar
  97. 97.
    Irie F, Jwa Hidari KIP, Tai T, Li Y-T, Seyama Y, Hirabayashi Y (1994) Biosynthetic pathway for a new series of gangliosides, GT1aα and GQ1bα. FEBS Lett 351(2):291–294. CrossRefPubMedGoogle Scholar
  98. 98.
    Proia RL (2003) Glycosphingolipid functions: insights from engineered mouse models. Philos Trans R Soc Lond B Biol Sci 358(1433):879–883PubMedCentralCrossRefPubMedGoogle Scholar
  99. 99.
    Kolter T, Proia RL, Sandhoff K (2002) Combinatorial ganglioside biosynthesis. J Biol Chem 277(29):25859–25862CrossRefPubMedGoogle Scholar
  100. 100.
    Sandhoff R (2010) Very long chain sphingolipids: tissue expression, function and synthesis. FEBS Lett 584(9):1907–1913. CrossRefPubMedGoogle Scholar
  101. 101.
    Bieberich E, MacKinnon S, Silva J, Li DD, Tencomnao T, Irwin L, Kapitonov D, Yu RK (2002) Regulation of ganglioside biosynthesis by enzyme complex formation of glycosyltransferases. Biochemistry 41(38):11479–11487CrossRefPubMedGoogle Scholar
  102. 102.
    Maccioni HJ, Quiroga R, Spessott W (2011) Organization of the synthesis of glycolipid oligosaccharides in the Golgi complex. FEBS Lett 585(11):1691–1698. CrossRefPubMedGoogle Scholar
  103. 103.
    Wennekes T, van den Berg RJ, Boot RG, van der Marel GA, Overkleeft HS, Aerts JM (2009) Glycosphingolipids—nature, function, and pharmacological modulation. Angew Chem Int Ed Engl 48(47):8848–8869. CrossRefPubMedGoogle Scholar
  104. 104.
    Merrill AH Jr, Wang E, Gilchrist DG, Riley RT (1993) Fumonisins and other inhibitors of de novo sphingolipid biosynthesis. Adv Lipid Res 26:215–234PubMedGoogle Scholar
  105. 105.
    Kolter T, Sandhoff K (1996) Inhibitors of glycosphingolipid biosynthesis. Chem Soc Rev 25:371–381CrossRefGoogle Scholar
  106. 106.
    Giraudo CG, Daniotti JL, Maccioni HJ (2001) Physical and functional association of glycolipid N-acetyl-galactosaminyl and galactosyl transferases in the Golgi apparatus. Proc Natl Acad Sci U S A 98(4):1625–1630. CrossRefPubMedCentralPubMedGoogle Scholar
  107. 107.
    Giraudo CG, Maccioni HJ (2003) Ganglioside glycosyltransferases organize in distinct multienzyme complexes in CHO-K1 cells. J Biol Chem 278(41):40262–40271. CrossRefPubMedGoogle Scholar
  108. 108.
    Uliana AS, Crespo PM, Martina JA, Daniotti JL, Maccioni HJ (2006) Modulation of GalT1 and SialT1 sub-Golgi localization by SialT2 expression reveals an organellar level of glycolipid synthesis control. J Biol Chem 281(43):32852–32860. CrossRefPubMedGoogle Scholar
  109. 109.
    Uliana AS, Giraudo CG, Maccioni HJ (2006) Cytoplasmic tails of SialT2 and GalNAcT impose their respective proximal and distal Golgi localization. Traffic 7(5):604–612. CrossRefPubMedGoogle Scholar
  110. 110.
    Scheel G, Acevedo E, Conzelmann E, Nehrkorn H, Sandhoff K (1982) 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 127(2):245–253CrossRefPubMedGoogle Scholar
  111. 111.
    Yamashita T, Wada R, Sasaki T, Deng C, Bierfreund U, Sandhoff K, Proia RL (1999) A vital role for glycosphingolipid synthesis during development and differentiation. Proc Natl Acad Sci U S A 96(16):9142–9147PubMedCentralCrossRefPubMedGoogle Scholar
  112. 112.
    Coetzee T, Fujita N, Dupree J, Shi R, Blight A, Suzuki K, Suzuki K, Popko B (1996) Myelination in the absence of galactocerebroside and sulfatide: normal structure with abnormal function and regional instability. Cell 86(2):209–219CrossRefPubMedGoogle Scholar
  113. 113.
    Bosio A, Binczek E, Stoffel W (1996) Functional breakdown of the lipid bilayer of the myelin membrane in central and peripheral nervous system by disrupted galactocerebroside synthesis. Proc Natl Acad Sci U S A 93(23):13280–13285PubMedCentralCrossRefPubMedGoogle Scholar
  114. 114.
    Takamiya K, Yamamoto A, Furukawa K, Yamashiro S, Shin M, Okada M, Fukumoto S, Haraguchi M, Takeda N, Fujimura K, Sakae M, Kishikawa M, Shiku H, Furukawa K, Aizawa S (1996) Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides but exhibit only subtle defects in their nervous system. Proc Natl Acad Sci U S A 93(20):10662–10667PubMedCentralCrossRefPubMedGoogle Scholar
  115. 115.
    Sheikh KA, Sun J, Liu Y, Kawai H, Crawford TA, Proia RL, Griffin JW, Schnaar RL (1999) Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Proc Natl Acad Sci U S A 96(13):7532–7537PubMedCentralCrossRefPubMedGoogle Scholar
  116. 116.
    Takamiya K, Yamamoto A, Furukawa K, Zhao J, Fukumoto S, Yamashiro S, Okada M, Haraguchi M, Shin M, Kishikawa M, Shiku H, Aizawa S, Furukawa K (1998) Complex gangliosides are essential in spermatogenesis of mice: possible roles in the transport of testosterone. Proc Natl Acad Sci U S A 95(21):12147–12152PubMedCentralCrossRefPubMedGoogle Scholar
  117. 117.
    Kawai H, Allende ML, Wada R, Kono M, Sango K, Deng C, Miyakawa T, Crawley JN, Werth N, Bierfreund U, Sandhoff K, Proia RL (2001) Mice expressing only monosialoganglioside GM3 exhibit lethal audiogenic seizures. J Biol Chem 276(10):6885–6888CrossRefPubMedGoogle Scholar
  118. 118.
    Chiavegatto S, Sun J, Nelson RJ, Schnaar RL (2000) A functional role for complex gangliosides: motor deficits in GM2/GD2 synthase knockout mice. Exp Neurol 166(2):227–234. CrossRefPubMedGoogle Scholar
  119. 119.
    Yamashita T, Hashiramoto A, Haluzik M, Mizukami H, Beck S, Norton A, Kono M, Tsuji S, Daniotti JL, Werth N, Sandhoff R, Sandhoff K, Proia RL (2003) Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc Natl Acad Sci U S A 100(6):3445–3449PubMedCentralCrossRefPubMedGoogle Scholar
  120. 120.
    Tagami S, Inokuchi Ji J, Kabayama K, Yoshimura H, Kitamura F, Uemura S, Ogawa C, Ishii A, Saito M, Ohtsuka Y, Sakaue S, Igarashi Y (2002) Ganglioside GM3 participates in the pathological conditions of insulin resistance. J Biol Chem 277(5):3085–3092. CrossRefPubMedGoogle Scholar
  121. 121.
    Yoon SJ, Nakayama K, Hikita T, Handa K, Hakomori SI (2006) Epidermal growth factor receptor tyrosine kinase is modulated by GM3 interaction with N-linked GlcNAc termini of the receptor. Proc Natl Acad Sci U S A 103(50):18987–18991. CrossRefPubMedCentralPubMedGoogle Scholar
  122. 122.
    Nordström V, Willershauser M, Herzer S, Rozman J, von Bohlen und Halbach O, Meldner S, Rothermel U, Kaden S, Roth FC, Waldeck C, Gretz N, de Angelis MH, Draguhn A, Klingenspor M, Gröne HJ, Jennemann R (2013) Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis. PLoS Biol 11(3):e1001506. CrossRefPubMedCentralPubMedGoogle Scholar
  123. 123.
    Proia RL (2004) Gangliosides help stabilize the brain. Nat Genet 36(11):1147–1148. CrossRefPubMedGoogle Scholar
  124. 124.
    Simpson MA, Cross H, Proukakis C, Priestman DA, Neville DC, Reinkensmeier G, Wang H, Wiznitzer M, Gurtz K, Verganelaki A, Pryde A, Patton MA, Dwek RA, Butters TD, Platt FM, Crosby AH (2004) Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet 36(11):1225–1229CrossRefPubMedGoogle Scholar
  125. 125.
    Boccuto L, Aoki K, Flanagan-Steet H, Chen CF, Fan X, Bartel F, Petukh M, Pittman A, Saul R, Chaubey A, Alexov E, Tiemeyer M, Steet R, Schwartz CE (2014) 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 23(2):418–433. CrossRefPubMedGoogle Scholar
  126. 126.
    Harlalka GV, Lehman A, Chioza B, Baple EL, Maroofian R, Cross H, Sreekantan-Nair A, Priestman DA, Al-Turki S, McEntagart ME, Proukakis C, Royle L, Kozak RP, Bastaki L, Patton M, Wagner K, Coblentz R, Price J, Mezei M, Schlade-Bartusiak K, Platt FM, Hurles ME, Crosby AH (2013) Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis. Brain 136(Pt 12):3618–3624. CrossRefPubMedCentralPubMedGoogle Scholar
  127. 127.
    Boukhris A, Schule R, Loureiro JL, Lourenco CM, Mundwiller E, Gonzalez MA, Charles P, Gauthier J, Rekik I, Acosta Lebrigio RF, Gaussen M, Speziani F, Ferbert A, Feki I, Caballero-Oteyza A, Dionne-Laporte A, Amri M, Noreau A, Forlani S, Cruz VT, Mochel F, Coutinho P, Dion P, Mhiri C, Schols L, Pouget J, Darios F, Rouleau GA, Marques W Jr, Brice A, Durr A, Zuchner S, Stevanin G (2013) Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am J Hum Genet 93(1):118–123. CrossRefPubMedCentralPubMedGoogle Scholar
  128. 128.
    Schwarzmann G, Hoffmann-Bleihauer P, Schubert J, Sandhoff K, Marsh D (1983) Incorporation of ganglioside analogues into fibroblast cell membranes. A spin-label study. Biochemistry 22(21):5041–5048CrossRefPubMedGoogle Scholar
  129. 129.
    Sonderfeld S, Conzelmann E, Schwarzmann G, Burg J, Hinrichs U, Sandhoff K (1985) Incorporation and metabolism of ganglioside GM2 in skin fibroblasts from normal and GM2 gangliosidosis subjects. Eur J Biochem 149(2):247–255CrossRefPubMedGoogle Scholar
  130. 130.
    Lucas M, Gershlick DC, Vidaurrazaga A, Rojas AL, Bonifacino JS, Hierro A (2016) Structural mechanism for cargo recognition by the retromer complex. Cell 167(6):1623–1635. e1614. CrossRefPubMedCentralPubMedGoogle Scholar
  131. 131.
    Ghidoni R, Trinchera M, Venerando B, Fiorilli A, Sonnino S, Tettamanti G (1986) Incorporation and metabolism of exogenous GM1 ganglioside in rat liver. Biochem J 237(1):147–155PubMedCentralCrossRefPubMedGoogle Scholar
  132. 132.
    Ghidoni R, Trinchera M, Sonnino S, Chigorno V, Tettamanti G (1987) The sialic acid residue of exogenous GM1 ganglioside is recycled for biosynthesis of sialoglycoconjugates in rat liver. Biochem J 247(1):157–164PubMedCentralCrossRefPubMedGoogle Scholar
  133. 133.
    Chinnapen DJ, Hsieh WT, te Welscher YM, Saslowsky DE, Kaoutzani L, Brandsma E, D'Auria L, Park H, Wagner JS, Drake KR, Kang M, Benjamin T, Ullman MD, Costello CE, Kenworthy AK, Baumgart T, Massol RH, Lencer WI (2012) Lipid sorting by ceramide structure from plasma membrane to ER for the cholera toxin receptor ganglioside GM1. Dev Cell 23(3):573–586. CrossRefPubMedCentralPubMedGoogle Scholar
  134. 134.
    Saslowsky DE, te Welscher YM, Chinnapen DJ, Wagner JS, Wan J, Kern E, Lencer WI (2013) Ganglioside GM1-mediated transcytosis of cholera toxin bypasses the retrograde pathway and depends on the structure of the ceramide domain. J Biol Chem 288(36):25804–25809. CrossRefPubMedCentralPubMedGoogle Scholar
  135. 135.
    Kok JW, Eskelinen S, Hoekstra K, Hoekstra D (1989) Salvage of glucosylceramide by recycling after internalization along the pathway of receptor-mediated endocytosis. Proc Natl Acad Sci U S A 86(24):9896–9900PubMedCentralCrossRefPubMedGoogle Scholar
  136. 136.
    Schwarzmann G, Hofmann P, Pütz U, Albrecht B (1995) Demonstration of direct glycosylation of nondegradable glucosylceramide analogs in cultured cells. J Biol Chem 270(36):21271–21276CrossRefPubMedGoogle Scholar
  137. 137.
    Gillard BK, Harrell RG, Marcus DM (1996) Pathways of glycosphingolipid biosynthesis in SW13 cells in the presence and absence of vimentin intermediate filaments. Glycobiology 6(1):33–42CrossRefPubMedGoogle Scholar
  138. 138.
    Tettamanti G (2004) Ganglioside/glycosphingolipid turnover: new concepts. Glycoconj J 20(5):301–317CrossRefPubMedGoogle Scholar
  139. 139.
    Tettamanti G, Bassi R, Viani P, Riboni L (2003) Salvage pathways in glycosphingolipid metabolism. Biochimie 85(3–4):423–437CrossRefPubMedGoogle Scholar
  140. 140.
    Wiegandt H (1985) Gangliosides. In: Wiegandt H (ed) Glycolipids. Elsevier Science Publishers B.V., New York, pp 199–247CrossRefGoogle Scholar
  141. 141.
    Krengel U, Bousquet PA (2014) Molecular recognition of gangliosides and their potential for cancer immunotherapies. Front Immunol 5:325. CrossRefPubMedCentralPubMedGoogle Scholar
  142. 142.
    Naito-Matsui Y, Davies LRL, Takematsu H, Chou H-H, Tangvoranuntakul P, Carlin AF, Verhagen A, Heyser CJ, Yoo S-W, Choudhury B, Paton JC, Paton AW, Varki NM, Schnaar RL, Varki A (2017) Physiological exploration of the long term evolutionary selection against expression of N-glycolylneuraminic acid in the brain. J Biol Chem 292(7):2557–2570. CrossRefPubMedCentralPubMedGoogle Scholar
  143. 143.
    Mlinac K, Fabris D, Vukelic Z, Rozman M, Heffer M, Bognar SK (2013) Structural analysis of brain ganglioside acetylation patterns in mice with altered ganglioside biosynthesis. Carbohydr Res 382:1–8. CrossRefPubMedGoogle Scholar
  144. 144.
    Manzi AE, Sjoberg ER, Diaz S, Varki A (1990) Biosynthesis and turnover of O-acetyl and N-acetyl groups in the gangliosides of human melanoma cells. J Biol Chem 265(22):13091–13103PubMedGoogle Scholar
  145. 145.
    Kohla G, Stockfleth E, Schauer R (2002) Gangliosides with O-acetylated sialic acids in tumors of neuroectodermal origin. Neurochem Res 27(7–8):583–592CrossRefPubMedGoogle Scholar
  146. 146.
    Watanabe K, Powell M, Hakomori S (1978) Isolation and characterization of a novel fucoganglioside of human erythrocyte membranes. J Biol Chem 253(24):8962–8967PubMedGoogle Scholar
  147. 147.
    Tokuda N, Zhang Q, Yoshida S, Kusunoki S, Urano T, Furukawa K, Furukawa K (2006) Genetic mechanisms for the synthesis of fucosyl GM1 in small cell lung cancer cell lines. Glycobiology 16(10):916–925. CrossRefPubMedGoogle Scholar
  148. 148.
    Hansson HA, Holmgren J, Svennerholm L (1977) Ultrastructural localization of cell membrane GM1 ganglioside by cholera toxin. Proc Natl Acad Sci U S A 74(9):3782–3786PubMedCentralCrossRefPubMedGoogle Scholar
  149. 149.
    Sonnino S, Prinetti A (2016) The role of sphingolipids in neuronal plasticity of the brain. J Neurochem 137(4):485–488. CrossRefPubMedGoogle Scholar
  150. 150.
    Gulbins E, Walter S, Becker KA, Halmer R, Liu Y, Reichel M, Edwards MJ, Muller CP, Fassbender K, Kornhuber J (2015) A central role for the acid sphingomyelinase/ceramide system in neurogenesis and major depression. J Neurochem 134(2):183–192. CrossRefPubMedGoogle Scholar
  151. 151.
    Sha S, Zhou L, Yin J, Takamiya K, Furukawa K, Furukawa K, Sokabe M, Chen L (2014) Deficits in cognitive function and hippocampal plasticity in GM2/GD2 synthase knockout mice. Hippocampus 24(4):369–382CrossRefPubMedGoogle Scholar
  152. 152.
    Ikarashi K, Fujiwara H, Yamazaki Y, Goto J, Kaneko K, Kato H, Fujii S, Sasaki H, Fukumoto S, Furukawa K, Waki H, Furukawa K (2011) Impaired hippocampal long-term potentiation and failure of learning in beta1,4-N-acetylgalactosaminyltransferase gene transgenic mice. Glycobiology 21(10):1373–1381. CrossRefPubMedGoogle Scholar
  153. 153.
    Svennerholm L, Gottfries CG (1994) Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (type I) and demyelination in late-onset form (type II). J Neurochem 62(3):1039–1047CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Shiozaki K, Takahashi K, Hosono M, Yamaguchi K, Hata K, Shiozaki M, Bassi R, Prinetti A, Sonnino S, Nitta K, Miyagi T (2015) Phosphatidic acid-mediated activation and translocation to the cell surface of sialidase NEU3, promoting signaling for cell migration. FASEB J 29(5):2099–2111. CrossRefPubMedGoogle Scholar
  155. 155.
    Shiga K, Takahashi K, Sato I, Kato K, Saijo S, Moriya S, Hosono M, Miyagi T (2015) Upregulation of sialidase NEU3 in head and neck squamous cell carcinoma associated with lymph node metastasis. Cancer science 106(11):1544–1553. CrossRefPubMedCentralPubMedGoogle Scholar
  156. 156.
    Takahashi K, Hosono M, Sato I, Hata K, Wada T, Yamaguchi K, Nitta K, Shima H, Miyagi T (2015) Sialidase NEU3 contributes neoplastic potential on colon cancer cells as a key modulator of gangliosides by regulating Wnt signaling. Int J Cancer 137(7):1560–1573. CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Kopitz J, von Reitzenstein C, Sinz K, Cantz M (1996) Selective ganglioside desialylation in the plasma membrane of human neuroblastoma cells. Glycobiology 6(3):367–376CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Papini N, Anastasia L, Tringali C, Croci G, Bresciani R, Yamaguchi K, Miyagi T, Preti A, Prinetti A, Prioni S, Sonnino S, Tettamanti G, Venerando B, Monti E (2004) The plasma membrane-associated sialidase MmNEU3 modifies the ganglioside pattern of adjacent cells supporting its involvement in cell-to-cell interactions. J Biol Chem 279(17):16989–16995. CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Sonnino S, Chigorno V, Aureli M, Masilamani AP, Valsecchi M, Loberto N, Prioni S, Mauri L, Prinetti A (2011) Role of gangliosides and plasma membrane-associated sialidase in the process of cell membrane organization. Adv Exp Med Biol 705:297–316. CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Sandhoff K, Pallmann B (1978) Membrane-bound neuraminidase from calf brain: regulation of oligosialoganglioside degradation by membrane fluidity and membrane components. Proc Natl Acad Sci U S A 75(1):122–126PubMedCentralCrossRefPubMedGoogle Scholar
  161. 161.
    Pellkofer R, Sandhoff K (1980) Halothane increases membrane fluidity and stimulates sphingomyelin degradation by membrane-bound neutral sphingomyelinase of synaptosomal plasma membranes from calf brain already at clinical concentrations. J Neurochem 34(4):988–992CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Anheuser S, Breiden B, Schwarzmann G, Sandhoff K (2015) Membrane lipids regulate ganglioside GM2 catabolism and GM2 activator protein activity. J Lipid Res 56(9):1747–1761. CrossRefPubMedCentralPubMedGoogle Scholar
  163. 163.
    Bierfreund U, Lemm T, Hoffmann A, Uhlhorn-Dierks G, Childs RA, Yuen CT, Feizi T, Sandhoff K (1999) 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 24(2):295–300CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Riboni L, Sonnino S, Acquotti D, Malesci A, Ghidoni R, Egge H, Mingrino S, Tettamanti G (1986) Natural occurrence of ganglioside lactones. Isolation and characterization of GD1b inner ester from adult human brain. J Biol Chem 261(18):8514–8519PubMedGoogle Scholar
  165. 165.
    Ledeen R, Wu G (2011) New findings on nuclear gangliosides: overview on metabolism and function. J Neurochem 116(5):714–720. CrossRefPubMedGoogle Scholar
  166. 166.
    Dyatlovitskaya EV, Bergelson LD (1987) Glycosphingolipids and antitumor immunity. Biochim Biophys Acta 907(2):125–143PubMedGoogle Scholar
  167. 167.
    Fredman P (1994) Gangliosides associated with primary brain tumors and their expression in cell lines established from these tumors. Prog Brain Res 101:225–240CrossRefPubMedGoogle Scholar
  168. 168.
    Ledeen RW, Wu G (2008) Nuclear sphingolipids: metabolism and signaling. J Lipid Res 49(6):1176–1186. CrossRefPubMedCentralPubMedGoogle Scholar
  169. 169.
    Henning R, Stoffel W (1973) Glycosphingolipids in lysosomal membranes. Hoppe Seylers Z Physiol Chem 354(7):760–770CrossRefPubMedGoogle Scholar
  170. 170.
    Fürst W, Sandhoff K (1992) Activator proteins and topology of lysosomal sphingolipid catabolism. Biochim Biophys Acta 1126(1):1–16CrossRefPubMedGoogle Scholar
  171. 171.
    Möbius W, Herzog V, Sandhoff K, Schwarzmann G (1999) Gangliosides are transported from the plasma membrane to intralysosomal membranes as revealed by immuno-electron microscopy. Biosci Rep 19(4):307–316CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Burkhardt JK, Hüttler S, Klein A, Möbius W, Habermann A, Griffiths G, Sandhoff K (1997) 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 73(1):10–18PubMedGoogle Scholar
  173. 173.
    Kolter T, Sandhoff K (2005) Principles of lysosomal membrane digestion: stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids. Annu Rev Cell Dev Biol 21:81–103CrossRefPubMedGoogle Scholar
  174. 174.
    Wollert T, Hurley JH (2010) Molecular mechanism of multivesicular body biogenesis by ESCRT complexes. Nature 464(7290):864–869PubMedCentralCrossRefPubMedGoogle Scholar
  175. 175.
    Florey O, Overholtzer M (2012) Autophagy proteins in macroendocytic engulfment. Trends Cell Biol 22(7):374–380PubMedCentralCrossRefPubMedGoogle Scholar
  176. 176.
    Gallala HD, Breiden B, Sandhoff K (2011) Regulation of the NPC2 protein-mediated cholesterol trafficking by membrane lipids. J Neurochem 116(5):702–707CrossRefPubMedGoogle Scholar
  177. 177.
    Quintern LE, Weitz G, Nehrkorn H, Tager JM, Schram AW, Sandhoff K (1987) Acid sphingomyelinase from human urine: purification and characterization. Biochim Biophys Acta 922(3):323–336CrossRefPubMedGoogle Scholar
  178. 178.
    Abdul-Hammed M, Breiden B, Adebayo MA, Babalola JO, Schwarzmann G, Sandhoff K (2010) Role of endosomal membrane lipids and NPC2 in cholesterol transfer and membrane fusion. J Lipid Res 51(7):1747–1760. CrossRefPubMedCentralPubMedGoogle Scholar
  179. 179.
    Gallala H, Sandhoff K (2011) Biological function of the cellular lipid BMP—BMP as a key activator for cholesterol sorting and membrane digestion. Neurochem Res 36(9):1594–1600CrossRefPubMedGoogle Scholar
  180. 180.
    Kolter T, Winau F, Schaible UE, Leippe M, Sandhoff K (2005) Lipid-binding proteins in membrane digestion, antigen presentation, and antimicrobial defense. J Biol Chem 280(50):41125–41128CrossRefPubMedGoogle Scholar
  181. 181.
    Appelqvist H, Sandin L, Bjornstrom K, Saftig P, Garner B, Ollinger K, Kagedal K (2012) Sensitivity to lysosome-dependent cell death is directly regulated by lysosomal cholesterol content. PLoS ONE 7(11):e50262. CrossRefPubMedCentralPubMedGoogle Scholar
  182. 182.
    Eskelinen EL, Tanaka Y, Saftig P (2003) At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol 13(3):137–145CrossRefPubMedGoogle Scholar
  183. 183.
    Kolter T, Sandhoff K (2010) Lysosomal degradation of membrane lipids. FEBS Lett 584(9):1700–1712CrossRefPubMedGoogle Scholar
  184. 184.
    Schuette CG, Pierstorff B, Huettler S, Sandhoff K (2001) Sphingolipid activator proteins: proteins with complex functions in lipid degradation and skin biogenesis. Glycobiology 11(6):81R–90RCrossRefPubMedGoogle Scholar
  185. 185.
    Kolter T, Sandhoff K (2006) Sphingolipid metabolism diseases. Biochim Biophys Acta 1758(12):2057–2079CrossRefPubMedGoogle Scholar
  186. 186.
    Schulze H, Sandhoff K (2014) Sphingolipids and lysosomal pathologies. Biochim Biophys Acta 1841(5):799–810. CrossRefPubMedGoogle Scholar
  187. 187.
    Sandhoff K, Harzer K (2013) Gangliosides and gangliosidoses: principles of molecular and metabolic pathogenesis. J Neurosci 33(25):10195–10208. CrossRefPubMedGoogle Scholar
  188. 188.
    Doering T, Holleran WM, Potratz A, Vielhaber G, Elias PM, Suzuki K, Sandhoff K (1999) Sphingolipid activator proteins are required for epidermal permeability barrier formation. J Biol Chem 274(16):11038–11045CrossRefPubMedGoogle Scholar
  189. 189.
    Hulkova H, Cervenkova M, Ledvinova J, Tochackova M, Hrebicek M, Poupetova H, Befekadu A, Berna L, Paton BC, Harzer K, Boor A, Smid F, Elleder M (2001) 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 10(9):927–940CrossRefPubMedGoogle Scholar
  190. 190.
    Monti E, Bonten E, D'Azzo A, Bresciani R, Venerando B, Borsani G, Schauer R, Tettamanti G (2010) Sialidases in vertebrates: a family of enzymes tailored for several cell functions. Adv Carbohydr Chem Biochem 64:403–479. CrossRefPubMedGoogle Scholar
  191. 191.
    Smutova V, Albohy A, Pan X, Korchagina E, Miyagi T, Bovin N, Cairo CW, Pshezhetsky AV (2014) Structural basis for substrate specificity of mammalian neuraminidases. PLoS ONE 9(9):e106320. CrossRefPubMedCentralPubMedGoogle Scholar
  192. 192.
    Timur ZK, Akyildiz Demir S, Marsching C, Sandhoff R, Seyrantepe V (2015) 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 4:72–82. CrossRefPubMedCentralPubMedGoogle Scholar
  193. 193.
    Bonten E, van der Spoel A, Fornerod M, Grosveld G, d'Azzo A (1996) Characterization of human lysosomal neuraminidase defines the molecular basis of the metabolic storage disorder sialidosis. Genes Dev 10(24):3156–3169CrossRefPubMedGoogle Scholar
  194. 194.
    d'Azzo A, Bonten E (2010) Molecular mechanisms of pathogenesis in a glycosphingolipid and a glycoprotein storage disease. Biochem Soc Trans 38(6):1453–1457. CrossRefPubMedCentralPubMedGoogle Scholar
  195. 195.
    Möbius W, Herzog V, Sandhoff K, Schwarzmann G (1999) Intracellular distribution of a biotin-labeled ganglioside, GM1, by immunoelectron microscopy after endocytosis in fibroblasts. J Histochem Cytochem 47(8):1005–1014CrossRefPubMedGoogle Scholar
  196. 196.
    Albrecht B, Pohlentz G, Sandhoff K, Schwarzmann G (1997) Synthesis and mass spectrometric characterization of digoxigenin and biotin labeled ganglioside GM1 and their uptake by and metabolism in cultured cells. Chem Phys Lipids 86(1):37–50CrossRefPubMedGoogle Scholar
  197. 197.
    Bradova V, Smid F, Ulrich-Bott B, Roggendorf W, Paton BC, Harzer K (1993) 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 92(2):143–152CrossRefPubMedGoogle Scholar
  198. 198.
    Harzer K, Paton BC, Poulos A, Kustermann-Kuhn B, Roggendorf W, Grisar T, Popp M (1989) 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 149(1):31–39CrossRefPubMedGoogle Scholar
  199. 199.
    Schnabel D, Schröder M, Fürst W, Klein A, Hurwitz R, Zenk T, Weber J, Harzer K, Paton BC, Poulos A et al (1992) 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 267(5):3312–3315PubMedGoogle Scholar
  200. 200.
    Möbius W, van Donselaar E, Ohno-Iwashita Y, Shimada Y, Heijnen HF, Slot JW, Geuze HJ (2003) Recycling compartments and the internal vesicles of multivesicular bodies harbor most of the cholesterol found in the endocytic pathway. Traffic 4(4):222–231CrossRefPubMedGoogle Scholar
  201. 201.
    Kobayashi T, Beuchat MH, Lindsay M, Frias S, Palmiter RD, Sakuraba H, Parton RG, Gruenberg J (1999) Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nat Cell Biol 1(2):113–118CrossRefPubMedGoogle Scholar
  202. 202.
    Oninla VO, Breiden B, Babalola JO, Sandhoff K (2014) Acid sphingomyelinase activity is regulated by membrane lipids and facilitates cholesterol transfer by NPC2. J Lipid Res 55(12):2606–2619. CrossRefPubMedCentralPubMedGoogle Scholar
  203. 203.
    Kölzer M, Werth N, Sandhoff K (2004) Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine. FEBS Lett 559(1–3):96–98CrossRefPubMedGoogle Scholar
  204. 204.
    Hurwitz R, Ferlinz K, Sandhoff K (1994) The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts. Biol Chem Hoppe Seyler 375(7):447–450CrossRefPubMedGoogle Scholar
  205. 205.
    Elojeimy S, Holman DH, Liu X, El-Zawahry A, Villani M, Cheng JC, Mahdy A, Zeidan Y, Bielwaska A, Hannun YA, Norris JS (2006) New insights on the use of desipramine as an inhibitor for acid ceramidase. FEBS Lett 580(19):4751–4756CrossRefPubMedGoogle Scholar
  206. 206.
    Lüllmann H, Lüllmann-Rauch R, Wassermann O (1978) Lipidosis induced by amphiphilic cationic drugs. Biochem Pharmacol 27(8):1103–1108CrossRefPubMedGoogle Scholar
  207. 207.
    Suzuki K, Chen GC (1968) GM1-gangliosidosis (generalized gangliosidosis). Morphology and chemical pathology. Pathol Eur 3(2):389–408PubMedGoogle Scholar
  208. 208.
    Fyrst H, Saba JD (2010) An update on sphingosine-1-phosphate and other sphingolipid mediators. Nat Chem Biol 6(7):489–497PubMedCentralCrossRefPubMedGoogle Scholar
  209. 209.
    Blom T, Li Z, Bittman R, Somerharju P, Ikonen E (2012) Tracking sphingosine metabolism and transport in sphingolipidoses: NPC1 deficiency as a test case. Traffic 13(9):1234–1243. CrossRefPubMedGoogle Scholar
  210. 210.
    van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9(2):112–124PubMedCentralCrossRefPubMedGoogle Scholar
  211. 211.
    Mouritsen OG, Zuckermann MJ (2004) What’s so special about cholesterol? Lipids 39(11):1101–1113CrossRefPubMedGoogle Scholar
  212. 212.
    Vanier MT (2015) Complex lipid trafficking in Niemann-Pick disease type C. J Inherit Metab Dis 38(1):187–199. CrossRefGoogle Scholar
  213. 213.
    Vanier MT, Millat G (2003) Niemann-Pick disease type C. Clin Genet 64(4):269–281CrossRefPubMedGoogle Scholar
  214. 214.
    Abdul-Hammed M, Breiden B, Schwarzmann G, Sandhoff K (2017) Lipids regulate the hydrolysis of membrane bound glucosylceramide by lysosomal β-glucocerebrosidase. J Lipid Res 58:563–577PubMedCentralCrossRefPubMedGoogle Scholar
  215. 215.
    Sandhoff K (2013) Metabolic and cellular bases of sphingolipidoses. Biochem Soc Trans 41(6):1562–1568. CrossRefPubMedGoogle Scholar
  216. 216.
    Ballabio A, Gieselmann V (2009) Lysosomal disorders: from storage to cellular damage. Biochim Biophys Acta 1793(4):684–696. CrossRefPubMedGoogle Scholar
  217. 217.
    Mizukami H, Mi Y, Wada R, Kono M, Yamashita T, Liu Y, Werth N, Sandhoff R, Sandhoff K, Proia RL (2002) Systemic inflammation in glucocerebrosidase-deficient mice with minimal glucosylceramide storage. J Clin Invest 109(9):1215–1221PubMedCentralCrossRefPubMedGoogle Scholar
  218. 218.
    Jeyakumar M, Thomas R, Elliot-Smith E, Smith DA, van der Spoel AC, d'Azzo A, Perry VH, Butters TD, Dwek RA, Platt FM (2003) Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain 126(Pt 4):974–987CrossRefPubMedGoogle Scholar
  219. 219.
    Conzelmann E, Sandhoff K (1983) Partial enzyme deficiencies: residual activities and the development of neurological disorders. Dev Neurosci 6(1):58–71CrossRefPubMedGoogle Scholar
  220. 220.
    Leinekugel P, Michel S, Conzelmann E, Sandhoff K (1992) Quantitative correlation between the residual activity of beta-hexosaminidase A and arylsulfatase A and the severity of the resulting lysosomal storage disease. Hum Genet 88(5):513–523CrossRefPubMedGoogle Scholar
  221. 221.
    Graber D, Salvayre R, Levade T (1994) Accurate differentiation of neuronopathic and nonneuronopathic forms of Niemann-Pick disease by evaluation of the effective residual lysosomal sphingomyelinase activity in intact cells. J Neurochem 63(3):1060–1068CrossRefPubMedGoogle Scholar
  222. 222.
    Meivar-Levy I, Horowitz M, Futerman AH (1994) Analysis of glucocerebrosidase activity using N-(1-[14C]hexanoyl)-D-erythroglucosylsphingosine demonstrates a correlation between levels of residual enzyme activity and the type of Gaucher disease. Biochem J 303(Pt 2):377–382PubMedCentralCrossRefPubMedGoogle Scholar
  223. 223.
    Sandhoff K (2016) Neuronal sphingolipidoses: membrane lipids and sphingolipid activator proteins regulate lysosomal sphingolipid catabolism. Biochimie 130:146–151. CrossRefPubMedGoogle Scholar
  224. 224.
    Vanier M (1983) Biochemical studies in Niemann-Pick disease: I. Major sphingolipids of liver and spleen. Biochim Biophys Acta 750:178–184CrossRefPubMedGoogle Scholar
  225. 225.
    Gondre-Lewis MC, McGlynn R, Walkley SU (2003) Cholesterol accumulation in NPC1-deficient neurons is ganglioside dependent. Curr Biol 13(15):1324–1329CrossRefPubMedGoogle Scholar
  226. 226.
    Cheruku SR, Xu Z, Dutia R, Lobel P, Storch J (2006) Mechanism of cholesterol transfer from the Niemann-Pick type C2 protein to model membranes supports a role in lysosomal cholesterol transport. J Biol Chem 281(42):31594–31604. CrossRefPubMedGoogle Scholar
  227. 227.
    Naureckiene S, Sleat DE, Lackland H, Fensom A, Vanier MT, Wattiaux R, Jadot M, Lobel P (2000) Identification of HE1 as the second gene of Niemann-Pick C disease. Science 290(5500):2298–2301CrossRefPubMedGoogle Scholar
  228. 228.
    Kwon HJ, Abi-Mosleh L, Wang ML, Deisenhofer J, Goldstein JL, Brown MS, Infante RE (2009) Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol. Cell 137(7):1213–1224PubMedCentralCrossRefPubMedGoogle Scholar
  229. 229.
    Locatelli-Hoops S, Remmel N, Klingenstein R, Breiden B, Rossocha M, Schoeniger M, Koenigs C, Saenger W, Sandhoff K (2006) 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 281(43):32451–32460CrossRefPubMedGoogle Scholar
  230. 230.
    Remmel N, Locatelli-Hoops S, Breiden B, Schwarzmann G, Sandhoff K (2007) 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 274(13):3405–3420CrossRefPubMedGoogle Scholar
  231. 231.
    Bowman EA, Walterfang M, Abel L, Desmond P, Fahey M, Velakoulis D (2015) Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann-Pick disease type C patients treated with miglustat. J Neurol 262(9):2106–2114. CrossRefPubMedGoogle Scholar
  232. 232.
    Patterson MC, Mengel E, Vanier MT, Schwierin B, Muller A, Cornelisse P, Pineda M, investigators NPCR, Amado-Fondo A, Amraoui Y, Andria G, Arellano M, Audoin B, Azcona C, Barr C, Baruteau J, Baumgartner C, Bell L, Bembi B, Benneddif K, Bernard G, Bobocea N, Bodzioch M, Boettcher T, Bonnan M, Broue P, Bruni A, Caceres M, Camino R, Campbell E, Cances C, Cannell P, Cesar J, Chabrol B, Chakrapani A, Colao R, Collet A, Corsetti T, Cousins A, Covanis A, Cox T, Cuisset JM, Dardis A, Das A, Deegan P, Dengler T, Deodato F, Derralynn H, Di Donato I, Di Rocco M, Dinopoulos A, DomanskaPakiela ES, Engelen M, Eyer D, Fecarotta S, Federico A, Filla A, Fiumara A, Fonseca MJ, Gabrielli O, Garcia T, Garrote J, Gissen P, Giugliani L, Greenberg C, Heron B, Hertzberg C, Higgins F, Hill A, Hiwot T, Hlavata A, Hörbe-Blindt A, Howley E, Hussain N, Illsinger S, Imrie J, Jacklin E, Jones S, Jovanovic A, Kaczmarek V, Kaphan E, Kibaek M, Kleinhans P, Klünemann KH, Koch SM, Koegl-Wallner W, Kolnikova M, Korenke GC, Korinthenberg R, Kumari S, Lachmann R, Lee Ann L, Likopoulou L, Lilienthal E, Link B, Lippold M, Lopez-Laso E, Luecke T, Lundgren J, Mackrell M, Madruga M, Maletta R, Malinova V, Manners J, Marinei R, Marquardt T, Martins E, Martins AM, Martins N, McAlister L, McCabe A, McKie M, McMahon S, Meehan M, Meldgaard Lund A, Mendozah C, Mengel E, Meyer A, Mielke S, Milligan A, Mir P, Moisa M, Mombelli C, Morris L, Müller vom Hagen J, Munoz B, Murphy E, Nagarajan L, Neto PB, Nevsimalova S, Nia S, Nicolai J, Niemann D, Niktari G, O'Callaghan MDM, Paucar-Arce M, Peers K, Peintinger L, Peralta M, Pérez J, Perez-Poyato M, Petrariu A, Pineda PA, Raiman J, Rask O, Rataj J, Raymond-Gaynor C, Reichelt G, Ribeiro E, Riches V, Roberts A, Roelants J, Rohrbach M, Rokicki D, Rolfs A, Russo C, Rutsch F, Saleem R, Santos M, Schmutz P, Schwahn B, Sedel F, Semotok J, Sharma R, Silska S, Silva A, Simmons L, Sivera R, Skorpen J, Sole G, Souza C, Stadlober-Degwerth M, Starling J, Temudo T, Tomas M, Tranchant C, Uziel G, Valayannopoulous V, Van den Hout H, Van der Tol L, Van Spronsen F, Vellodi A, Verdu A, Vilchez JJ, Vinaixa A, Visser G, Voelker J, Waldek S, Walter A, Walterfang M, Wein U, Widner H, Wilcke C, Wildish L, Wraith E, Wright N, Xaidara A, Yamamoto M, Zallocco F, Zielke S (2015) 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 10:65PubMedCentralCrossRefPubMedGoogle Scholar
  233. 233.
    Schwarzmann G, Breiden B, Sandhoff K (2015) Membrane-spanning lipids for an uncompromised monitoring of membrane fusion and intermembrane lipid transfer. J Lipid Res 56(10):1861–1879. CrossRefPubMedCentralPubMedGoogle Scholar
  234. 234.
    Vaccaro AM, Tatti M, Ciaffoni F, Salvioli R, Serafino A, Barca A (1994) Saposin-C induces pH-dependent destabilization and fusion of phosphatidylserine-containing vesicles. FEBS Lett 349(2):181–186CrossRefPubMedGoogle Scholar
  235. 235.
    Conzelmann E, Burg J, Stephan G, Sandhoff K (1982) Complexing of glycolipids and their transfer between membranes by the activator protein for degradation of lysosomal ganglioside GM2. Eur J Biochem 123(2):455–464CrossRefPubMedGoogle Scholar
  236. 236.
    Wilkening G, Linke T, Sandhoff K (1998) Lysosomal degradation on vesicular membrane surfaces. Enhanced glucosylceramide degradation by lysosomal anionic lipids and activators. J Biol Chem 273(46):30271–30278CrossRefPubMedGoogle Scholar
  237. 237.
    Sarmientos F, Schwarzmann G, Sandhoff K (1986) Specificity of human glucosylceramide beta-glucosidase towards synthetic glucosylsphingolipids inserted into liposomes. Kinetic studies in a detergent-free assay system. Eur J Biochem 160(3):527–535CrossRefPubMedGoogle Scholar
  238. 238.
    Murugesan V, Chuang WL, Liu J, Lischuk A, Kacena K, Lin H, Pastores GM, Yang R, Keutzer J, Zhang K, Mistry PK (2016) Glucosylsphingosine is a key biomarker of Gaucher disease. Am J Hematol 91(11):1082–1089. CrossRefPubMedCentralPubMedGoogle Scholar
  239. 239.
    Linke T, Wilkening G, Lansmann S, Moczall H, Bartelsen O, Weisgerber J, Sandhoff K (2001) Stimulation of acid sphingomyelinase activity by lysosomal lipids and sphingolipid activator proteins. Biol Chem 382(2):283–290CrossRefPubMedGoogle Scholar
  240. 240.
    Linke T, Wilkening G, Sadeghlar F, Mozcall H, Bernardo K, Schuchman E, Sandhoff K (2001) Interfacial regulation of acid ceramidase activity. Stimulation of ceramide degradation by lysosomal lipids and sphingolipid activator proteins. J Biol Chem 276(8):5760–5768CrossRefPubMedGoogle Scholar
  241. 241.
    Graf CG, Schulz C, Schmälzlein M, Heinlein C, Mönnich M, Perkams L, Püttner M, Boos I, Hessefort M, Lombana Sanchez JN, Weyand M, Steegborn C, Breiden B, Ross K, Schwarzmann G, Sandhoff K, Unverzagt C (2017) Synthetic glycoforms reveal carbohydrate-dependent bioactivity of human saposin D. Angew Chem Int Ed Engl 56:5252–5257. CrossRefPubMedGoogle Scholar
  242. 242.
    Breiden B, Sandhoff K (2014) The role of sphingolipid metabolism in cutaneous permeability barrier formation. Biochim Biophys Acta 1841(3):441–452. CrossRefPubMedGoogle Scholar
  243. 243.
    Henseler M, Klein A, Glombitza GJ, Suzuki K, Sandhoff K (1996) Expression of the three alternative forms of the sphingolipid activator protein precursor in baby hamster kidney cells and functional assays in a cell culture system. J Biol Chem 271(14):8416–8423CrossRefPubMedGoogle Scholar
  244. 244.
    Tamargo RJ, Velayati A, Goldin E, Sidransky E (2012) The role of saposin C in Gaucher disease. Mol Genet Metab 106(3):257–263PubMedCentralCrossRefPubMedGoogle Scholar
  245. 245.
    Geiger B, Arnon R, Sandhoff K (1977) Immunochemical and biochemical investigation of hexosaminidase S. Am J Hum Genet 29(5):508–522PubMedCentralPubMedGoogle Scholar
  246. 246.
    Svennerholm L (1962) The chemical structure of normal human brain and Tay-Sachs gangliosides. Biochem Biophys Res Commun 9:436–441CrossRefPubMedGoogle Scholar
  247. 247.
    van Echten G, Sandhoff K (1989) Modulation of ganglioside biosynthesis in primary cultured neurons. J Neurochem 52(1):207–214CrossRefPubMedGoogle Scholar
  248. 248.
    Wilkening G, Linke T, Uhlhorn-Dierks G, Sandhoff K (2000) Degradation of membrane-bound ganglioside GM1. Stimulation by bis(monoacylglycero)phosphate and the activator proteins SAP-B and GM2-AP. J Biol Chem 275(46):35814–35819CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.LIMES Institute, Membrane Biology & Lipid Biochemistry Unit, Kekulé-Institut für Organische Chemie und BiochemieUniversität BonnBonnGermany

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