SpringerLink
Log in

Ganglioside Metabolism and Its Inherited Diseases

  • Protocol
  • First Online:
Gangliosides

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1804))

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Protocol
USD 49.95
Price excludes VAT (Brazil)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (Brazil)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (Brazil)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (Brazil)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Notes

  1. 1.

    Also known as ST3Gal V or sialyltransferase 9 (Siat 9).

  2. 2.

    Also known as ST3Gal V or sialyltransferase 9 (Siat 9) or SAT-I.

  3. 3.

    Also known as α-2,8-sialyltransferase (Siat 8) or SAT II.

  4. 4.

    Synonyms are GalNAcT, GM2/GD2 synthase.

  5. 5.

    Also known as GalT II.

  6. 6.

    Synonyms are SAT IVB, GD1a/GT1b synthase.

  7. 7.

    Synonyms St3Gal I, SAT IV.

  8. 8.

    Synonyms are SAT V, GT1a/GQ1b synthase.

  9. 9.

    Also known as α-2,6-sialyltransferase, SAT VIIc-f.

References

  1. Thudichum JLW (1884) A treatise on the chemical constitution of the brain. London, Bailliere, Tindall and Cox

    Google Scholar 

  2. Klenk E (1939) Niemann-Pick’sche Krankheit und Amaurotische Idiotie. Hoppe-Seyler’s Z Physiol Chem 262:128–143

    Article  CAS  Google Scholar 

  3. Klenk E (1942) Über die Ganglioside, eine neue Gruppe von zuckerhaltigen Gehirnlipoiden. Hoppe Seyler’s Z Physiol Chem 273:76–86

    Article  CAS  Google Scholar 

  4. Kuhn R, Wiegandt H (1963) Die Konstitution der Ganglio-N-tetraose und des Gangliosids GI. Chem Ber 96:866–880

    Article  CAS  Google Scholar 

  5. Jatzkewitz H, Sandhoff K (1963) On a biochemically special form of infantile amaurotic idiocy. Biochim Biophys Acta 70:354–356

    Article  CAS  PubMed  Google Scholar 

  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):2469–2489

    Article  CAS  PubMed  Google Scholar 

  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):1279–1282

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.jmb.2016.06.013

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/978-1-4939-1154-7_10

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1471-4159.2010.07019.x

    Article  CAS  PubMed  Google Scholar 

  11. Sandhoff K (2012) My journey into the world of sphingolipids and sphingolipidoses. Proc Jpn Acad Ser B 88:554–582

    Article  CAS  Google Scholar 

  12. Mehl E, Jatzkewitz H (1964) Eine cerebrosidsulfatase aus Schweineniere. Hoppe-Seylers. Zeitschr Physiol Chem 339(1–6):260–276

    Article  CAS  Google Scholar 

  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):3979–3983

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  14. Yamakawa T (1996) A reflection on the early history of glycosphingolipids. Glycoconj J 13(2):123–126. https://doi.org/10.1007/bf00731485

    Article  CAS  PubMed  Google Scholar 

  15. Wiegandt H (1968) The structure and the function of gangliosides. Angew Chem Int Ed Engl 7(2):87–96. https://doi.org/10.1002/anie.196800871

    Article  CAS  PubMed  Google Scholar 

  16. Wiegandt H (1995) The chemical constitution of gangliosides of the vertebrate nervous system. Behav Brain Res 66(1–2):85–97

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1074/jbc.M502775200

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.febslet.2009.12.010

    Article  CAS  PubMed  Google Scholar 

  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):12459–12464

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):2725–2730

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):506–520

    Article  CAS  PubMed  Google Scholar 

  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):2703–2707

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  23. Kolter T, Magin TM, Sandhoff K (2000) Biomolecule function: no reliable prediction from cell culture. Traffic 1(10):803–804

    Article  CAS  PubMed  Google Scholar 

  24. Schnaar RL (2010) Brain gangliosides in axon-myelin stability and axon regeneration. FEBS Lett 584(9):1741–1747. https://doi.org/10.1016/j.febslet.2009.10.011

    Article  CAS  PubMed  Google Scholar 

  25. Merrill AH Jr (2002) De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J Biol Chem 277(29):25843–25846. https://doi.org/10.1074/jbc.R200009200

    Article  CAS  PubMed  Google Scholar 

  26. Merrill AH Jr (2011) Sphingolipid and glycosphingolipid metabolic pathways in the era of sphingolipidomics. Chem Rev 111(10):6387–6422. https://doi.org/10.1021/cr2002917

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):14–20

    Article  CAS  PubMed  Google Scholar 

  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):22432–22437

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.cmet.2007.01.002

    Article  CAS  PubMed  Google Scholar 

  30. Hanada K (2003) Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. Biochim Biophys Acta 1632(1–3):16–30

    Article  CAS  PubMed  Google Scholar 

  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):63–77

    Article  CAS  PubMed  Google Scholar 

  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):230–235

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1073/pnas.1516733112

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1007/s00415-011-6397-y

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1007/s10545-014-9736-1

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1074/jbc.M109.092973

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.M808798200

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1172/JCI57549

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1194/jlr.M072421

    Article  CAS  PubMed  Google Scholar 

  40. Mullen TD, Hannun YA, Obeid LM (2012) Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochem J 441(3):789–802. https://doi.org/10.1042/BJ20111626

    Article  PubMed  CAS  Google Scholar 

  41. Grosch S, Schiffmann S, Geisslinger G (2012) Chain length-specific properties of ceramides. Prog Lipid Res 51(1):50–62. https://doi.org/10.1016/j.plipres.2011.11.001

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1074/jbc.M115.695858

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  43. Yu RK, Bieberich E, **a T, Zeng G (2004) Regulation of ganglioside biosynthesis in the nervous system. J Lipid Res 45(5):783–793. https://doi.org/10.1194/jlr.R300020-JLR200

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.plipres.2016.03.006

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1194/jlr.M009142

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1002/acn3.28

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.M113.479907

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.cmet.2014.08.002

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1074/jbc.M112.413500

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1371/journal.pgen.1002063

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1073/pnas.1522071113

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.M115.691212

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1093/hmg/ddr494

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/hmg/ddv204

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/jid.2013.153

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pgen.1003536

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):33549–33560

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.M109.077610

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.M109.077594

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1194/jlr.M022715

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.M112.402719

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.M111.261206

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1530/ERC-15-0058

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  64. Ledeen RW, Yu RK, Eng LF (1973) Gangliosides of human myelin: sialosylgalactosylceramide (G7) as a major component. J Neurochem 21(4):829–839

    Article  CAS  PubMed  Google Scholar 

  65. Mullin BR, Patrick DH, Poore CM, Smith MT (1984) Prevention of experimental allergic encephalomyelitis by ganglioside GM4. Brain Res 296(1):174–176

    Article  CAS  PubMed  Google Scholar 

  66. Coste H, Martel MB, Got R (1986) Topology of glucosylceramide synthesis in Golgi membranes from porcine submaxillary glands. Biochim Biophys Acta 858(1):6–12

    Article  CAS  PubMed  Google Scholar 

  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):259–267

    Article  CAS  PubMed  Google Scholar 

  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):4638–4643

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  69. Futerman AH, Pagano RE (1991) Determination of the intracellular sites and topology of glucosylceramide synthesis in rat liver. Biochem J 280(2):295–302

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):451–456

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nature12423

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.bbalip.2007.04.004

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/nature02188

    Article  CAS  PubMed  Google Scholar 

  74. Lannert H, Bünning C, Jeckel D, Wieland FT (1994) Lactosylceramide is synthesized in the lumen of the Golgi apparatus. FEBS Lett 342(1):91–96

    Article  CAS  PubMed  Google Scholar 

  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):13106–13115

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1042/BJ20050047

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):2939–2946

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/glycob/cwt054

    Article  CAS  PubMed  Google Scholar 

  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):62–67

    Article  CAS  PubMed  Google Scholar 

  80. Roseman S (1970) The synthesis of complex carbohydrates by multiglycosyltransferase systems and their potential function in intercellular adhesion. Chem Phys Lipids 5(1):270–297

    Article  CAS  PubMed  Google Scholar 

  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):47–54

    Article  CAS  PubMed  Google Scholar 

  82. Yusuf HK, Pohlentz G, Sandhoff K (1984) Ganglioside biosynthesis in Golgi apparatus: new perspectives on its mechanism. J Neurosci Res 12(2–3):161–178

    Article  CAS  PubMed  Google Scholar 

  83. Simons K, Gerl MJ (2010) Revitalizing membrane rafts: new tools and insights. Nat Rev Mol Cell Biol 11(10):688–699. https://doi.org/10.1038/nrm2977

    Article  CAS  PubMed  Google Scholar 

  84. Simons K, Toomre D (2000) Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1(1):31–39. https://doi.org/10.1038/35036052

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/S0006-3495(00)76592-1

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1038/nature02013

    Article  CAS  PubMed  Google Scholar 

  87. Mukherjee S, Maxfield FR (2000) Role of membrane organization and membrane domains in endocytic lipid trafficking. Traffic 1(3):203–211

    Article  CAS  PubMed  Google Scholar 

  88. Spessott W, Crespo PM, Daniotti JL, Maccioni HJ (2012) Glycosyltransferase complexes improve glycolipid synthesis. FEBS Lett 586(16):2346–2350. https://doi.org/10.1016/j.febslet.2012.05.041

    Article  CAS  PubMed  Google Scholar 

  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):310–315

    CAS  PubMed  Google Scholar 

  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):5804–5807

    CAS  PubMed  Google Scholar 

  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):55–63

    Article  CAS  PubMed  Google Scholar 

  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):7044–7048

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):137–142

    Article  CAS  PubMed  Google Scholar 

  94. Iber H, Sandhoff K (1989) Identity of GD1C, GT1a and GQ1b synthase in Golgi vesicles from rat liver. FEBS Lett 254(1–2):124–128

    Article  CAS  PubMed  Google Scholar 

  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):115–120

    Article  CAS  PubMed  Google Scholar 

  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):1533–1537

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/0014-5793(94)00883-3

    Article  CAS  PubMed  Google Scholar 

  98. Proia RL (2003) Glycosphingolipid functions: insights from engineered mouse models. Philos Trans R Soc Lond B Biol Sci 358(1433):879–883

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  99. Kolter T, Proia RL, Sandhoff K (2002) Combinatorial ganglioside biosynthesis. J Biol Chem 277(29):25859–25862

    Article  CAS  PubMed  Google Scholar 

  100. Sandhoff R (2010) Very long chain sphingolipids: tissue expression, function and synthesis. FEBS Lett 584(9):1907–1913. https://doi.org/10.1016/j.febslet.2009.12.032

    Article  CAS  PubMed  Google Scholar 

  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):11479–11487

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.febslet.2011.03.030

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/anie.200902620

    Article  CAS  PubMed  Google Scholar 

  104. Merrill AH Jr, Wang E, Gilchrist DG, Riley RT (1993) Fumonisins and other inhibitors of de novo sphingolipid biosynthesis. Adv Lipid Res 26:215–234

    CAS  PubMed  Google Scholar 

  105. Kolter T, Sandhoff K (1996) Inhibitors of glycosphingolipid biosynthesis. Chem Soc Rev 25:371–381

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1073/pnas.031458398

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  107. Giraudo CG, Maccioni HJ (2003) Ganglioside glycosyltransferases organize in distinct multienzyme complexes in CHO-K1 cells. J Biol Chem 278(41):40262–40271. https://doi.org/10.1074/jbc.M305455200

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1074/jbc.M605805200

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1600-0854.2006.00413.x

    Article  CAS  PubMed  Google Scholar 

  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):245–253

    Article  CAS  PubMed  Google Scholar 

  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):9142–9147

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):209–219

    Article  CAS  PubMed  Google Scholar 

  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):13280–13285

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):10662–10667

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):7532–7537

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):12147–12152

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):6885–6888

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1006/exnr.2000.7504

    Article  CAS  PubMed  Google Scholar 

  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):3445–3449

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.M103705200

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1073/pnas.0609281103

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1371/journal.pbio.1001506

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  123. Proia RL (2004) Gangliosides help stabilize the brain. Nat Genet 36(11):1147–1148. https://doi.org/10.1038/ng1104-1147

    Article  CAS  PubMed  Google Scholar 

  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):1225–1229

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/hmg/ddt434

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/brain/awt270

    Article  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.ajhg.2013.05.006

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):5041–5048

    Article  CAS  PubMed  Google Scholar 

  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):247–255

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.cell.2016.10.056

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):147–155

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):157–164

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.devcel.2012.08.002

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.M113.474957

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):9896–9900

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):21271–21276

    Article  CAS  PubMed  Google Scholar 

  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):33–42

    Article  CAS  PubMed  Google Scholar 

  138. Tettamanti G (2004) Ganglioside/glycosphingolipid turnover: new concepts. Glycoconj J 20(5):301–317

    Article  CAS  PubMed  Google Scholar 

  139. Tettamanti G, Bassi R, Viani P, Riboni L (2003) Salvage pathways in glycosphingolipid metabolism. Biochimie 85(3–4):423–437

    Article  CAS  PubMed  Google Scholar 

  140. Wiegandt H (1985) Gangliosides. In: Wiegandt H (ed) Glycolipids. Elsevier Science Publishers B.V., New York, pp 199–247

    Chapter  Google Scholar 

  141. Krengel U, Bousquet PA (2014) Molecular recognition of gangliosides and their potential for cancer immunotherapies. Front Immunol 5:325. https://doi.org/10.3389/fimmu.2014.00325

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.M116.768531

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.carres.2013.09.007

    Article  CAS  PubMed  Google Scholar 

  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):13091–13103

    CAS  PubMed  Google Scholar 

  145. Kohla G, Stockfleth E, Schauer R (2002) Gangliosides with O-acetylated sialic acids in tumors of neuroectodermal origin. Neurochem Res 27(7–8):583–592

    Article  CAS  PubMed  Google Scholar 

  146. Watanabe K, Powell M, Hakomori S (1978) Isolation and characterization of a novel fucoganglioside of human erythrocyte membranes. J Biol Chem 253(24):8962–8967

    CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/glycob/cwl022

    Article  CAS  PubMed  Google Scholar 

  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):3782–3786

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  149. Sonnino S, Prinetti A (2016) The role of sphingolipids in neuronal plasticity of the brain. J Neurochem 137(4):485–488. https://doi.org/10.1111/jnc.13589

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1111/jnc.13145

    Article  CAS  PubMed  Google Scholar 

  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):369–382

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/glycob/cwr090

    Article  CAS  PubMed  Google Scholar 

  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):1039–1047

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1096/fj.14-262543

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1111/cas.12810

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1002/ijc.29527

    Article  PubMed  CAS  Google Scholar 

  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):367–376

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1074/jbc.M400881200

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1007/978-1-4419-7877-6_14

    Article  PubMed  CAS  Google Scholar 

  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):122–126

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):988–992

    Article  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1194/jlr.M061036

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):295–300

    Article  PubMed  CAS  Google Scholar 

  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):8514–8519

    CAS  PubMed  Google Scholar 

  165. Ledeen R, Wu G (2011) New findings on nuclear gangliosides: overview on metabolism and function. J Neurochem 116(5):714–720. https://doi.org/10.1111/j.1471-4159.2010.07115.x

    Article  CAS  PubMed  Google Scholar 

  166. Dyatlovitskaya EV, Bergelson LD (1987) Glycosphingolipids and antitumor immunity. Biochim Biophys Acta 907(2):125–143

    CAS  PubMed  Google Scholar 

  167. Fredman P (1994) Gangliosides associated with primary brain tumors and their expression in cell lines established from these tumors. Prog Brain Res 101:225–240

    Article  CAS  PubMed  Google Scholar 

  168. Ledeen RW, Wu G (2008) Nuclear sphingolipids: metabolism and signaling. J Lipid Res 49(6):1176–1186. https://doi.org/10.1194/jlr.R800009-JLR200

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  169. Henning R, Stoffel W (1973) Glycosphingolipids in lysosomal membranes. Hoppe Seylers Z Physiol Chem 354(7):760–770

    Article  CAS  PubMed  Google Scholar 

  170. Fürst W, Sandhoff K (1992) Activator proteins and topology of lysosomal sphingolipid catabolism. Biochim Biophys Acta 1126(1):1–16

    Article  PubMed  Google Scholar 

  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):307–316

    Article  PubMed  Google Scholar 

  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):10–18

    CAS  PubMed  Google Scholar 

  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 21:81–103

    Article  CAS  PubMed  Google Scholar 

  174. Wollert T, Hurley JH (2010) Molecular mechanism of multivesicular body biogenesis by ESCRT complexes. Nature 464(7290):864–869

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  175. Florey O, Overholtzer M (2012) Autophagy proteins in macroendocytic engulfment. Trends Cell Biol 22(7):374–380

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  176. Gallala HD, Breiden B, Sandhoff K (2011) Regulation of the NPC2 protein-mediated cholesterol trafficking by membrane lipids. J Neurochem 116(5):702–707

    Article  CAS  PubMed  Google Scholar 

  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):323–336

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1194/jlr.M003822

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):1594–1600

    Article  CAS  PubMed  Google Scholar 

  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):41125–41128

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0050262

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  182. Eskelinen EL, Tanaka Y, Saftig P (2003) At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol 13(3):137–145

    Article  CAS  PubMed  Google Scholar 

  183. Kolter T, Sandhoff K (2010) Lysosomal degradation of membrane lipids. FEBS Lett 584(9):1700–1712

    Article  CAS  PubMed  Google Scholar 

  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–90R

    Article  CAS  PubMed  Google Scholar 

  185. Kolter T, Sandhoff K (2006) Sphingolipid metabolism diseases. Biochim Biophys Acta 1758(12):2057–2079

    Article  CAS  PubMed  Google Scholar 

  186. Schulze H, Sandhoff K (2014) Sphingolipids and lysosomal pathologies. Biochim Biophys Acta 1841(5):799–810. https://doi.org/10.1016/j.bbalip.2013.10.015

    Article  CAS  PubMed  Google Scholar 

  187. Sandhoff K, Harzer K (2013) Gangliosides and gangliosidoses: principles of molecular and metabolic pathogenesis. J Neurosci 33(25):10195–10208. https://doi.org/10.1523/JNEUROSCI.0822-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):11038–11045

    Article  CAS  PubMed  Google Scholar 

  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):927–940

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/S0065-2318(10)64007-3

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0106320

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.ymgmr.2015.07.004

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):3156–3169

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1042/BST0381453

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):1005–1014

    Article  PubMed  Google Scholar 

  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):37–50

    Article  CAS  PubMed  Google Scholar 

  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):143–152

    Article  CAS  PubMed  Google Scholar 

  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):31–39

    Article  CAS  PubMed  Google Scholar 

  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):3312–3315

    CAS  PubMed  Google Scholar 

  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):222–231

    Article  PubMed  Google Scholar 

  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):113–118

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1194/jlr.M054528

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):96–98

    Article  CAS  PubMed  Google Scholar 

  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):447–450

    Article  CAS  PubMed  Google Scholar 

  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):4751–4756

    Article  CAS  PubMed  Google Scholar 

  206. Lüllmann H, Lüllmann-Rauch R, Wassermann O (1978) Lipidosis induced by amphiphilic cationic drugs. Biochem Pharmacol 27(8):1103–1108

    Article  PubMed  Google Scholar 

  207. Suzuki K, Chen GC (1968) GM1-gangliosidosis (generalized gangliosidosis). Morphology and chemical pathology. Pathol Eur 3(2):389–408

    CAS  PubMed  Google Scholar 

  208. Fyrst H, Saba JD (2010) An update on sphingosine-1-phosphate and other sphingolipid mediators. Nat Chem Biol 6(7):489–497

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1111/j.1600-0854.2012.01379.x

    Article  CAS  PubMed  Google Scholar 

  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):112–124

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  211. Mouritsen OG, Zuckermann MJ (2004) What’s so special about cholesterol? Lipids 39(11):1101–1113

    Article  CAS  PubMed  Google Scholar 

  212. Vanier MT (2015) Complex lipid trafficking in Niemann-Pick disease type C. J Inherit Metab Dis 38(1):187–199. https://doi.org/10.1007/s10545-014-9794-4

    Article  CAS  PubMed  Google Scholar 

  213. Vanier MT, Millat G (2003) Niemann-Pick disease type C. Clin Genet 64(4):269–281

    Article  CAS  PubMed  Google Scholar 

  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 58:563–577

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  215. Sandhoff K (2013) Metabolic and cellular bases of sphingolipidoses. Biochem Soc Trans 41(6):1562–1568. https://doi.org/10.1042/BST20130083

    Article  CAS  PubMed  Google Scholar 

  216. Ballabio A, Gieselmann V (2009) Lysosomal disorders: from storage to cellular damage. Biochim Biophys Acta 1793(4):684–696. https://doi.org/10.1016/j.bbamcr.2008.12.001

    Article  CAS  PubMed  Google Scholar 

  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):1215–1221

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):974–987

    Article  CAS  PubMed  Google Scholar 

  219. Conzelmann E, Sandhoff K (1983) Partial enzyme deficiencies: residual activities and the development of neurological disorders. Dev Neurosci 6(1):58–71

    Article  PubMed  Google Scholar 

  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):513–523

    Article  CAS  PubMed  Google Scholar 

  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):1060–1068

    Article  CAS  PubMed  Google Scholar 

  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):377–382

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  223. Sandhoff K (2016) Neuronal sphingolipidoses: membrane lipids and sphingolipid activator proteins regulate lysosomal sphingolipid catabolism. Biochimie 130:146–151. https://doi.org/10.1016/j.biochi.2016.05.004

    Article  CAS  PubMed  Google Scholar 

  224. Vanier M (1983) Biochemical studies in Niemann-Pick disease: I. Major sphingolipids of liver and spleen. Biochim Biophys Acta 750:178–184

    Article  CAS  PubMed  Google Scholar 

  225. Gondre-Lewis MC, McGlynn R, Walkley SU (2003) Cholesterol accumulation in NPC1-deficient neurons is ganglioside dependent. Curr Biol 13(15):1324–1329

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1074/jbc.M602765200

    Article  CAS  PubMed  Google Scholar 

  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):2298–2301

    Article  CAS  PubMed  Google Scholar 

  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):1213–1224

    Article  PubMed Central  PubMed  Google Scholar 

  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):32451–32460

    Article  CAS  PubMed  Google Scholar 

  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):3405–3420

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s00415-015-7819-z

    Article  CAS  PubMed  Google Scholar 

  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 10:65

    Article  PubMed Central  PubMed  Google Scholar 

  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. https://doi.org/10.1194/jlr.M056929

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):181–186

    Article  CAS  PubMed  Google Scholar 

  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):455–464

    Article  CAS  PubMed  Google Scholar 

  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):30271–30278

    Article  CAS  PubMed  Google Scholar 

  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):527–535

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/ajh.24491

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  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):283–290

    Article  CAS  PubMed  Google Scholar 

  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):5760–5768

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/anie.201701362

    Article  CAS  PubMed  Google Scholar 

  242. Breiden B, Sandhoff K (2014) The role of sphingolipid metabolism in cutaneous permeability barrier formation. Biochim Biophys Acta 1841(3):441–452. https://doi.org/10.1016/j.bbalip.2013.08.010

    Article  CAS  PubMed  Google Scholar 

  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):8416–8423

    Article  CAS  PubMed  Google Scholar 

  244. Tamargo RJ, Velayati A, Goldin E, Sidransky E (2012) The role of saposin C in Gaucher disease. Mol Genet Metab 106(3):257–263

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  245. Geiger B, Arnon R, Sandhoff K (1977) Immunochemical and biochemical investigation of hexosaminidase S. Am J Hum Genet 29(5):508–522

    PubMed Central  PubMed  CAS  Google Scholar 

  246. Svennerholm L (1962) The chemical structure of normal human brain and Tay-Sachs gangliosides. Biochem Biophys Res Commun 9:436–441

    Article  CAS  PubMed  Google Scholar 

  247. van Echten G, Sandhoff K (1989) Modulation of ganglioside biosynthesis in primary cultured neurons. J Neurochem 52(1):207–214

    Article  PubMed  Google Scholar 

  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):35814–35819

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. LIMES Institute, Membrane Biology & Lipid Biochemistry Unit, Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Bonn, Germany

    Bernadette Breiden & Konrad Sandhoff

Authors
  1. Bernadette Breiden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Konrad Sandhoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Konrad Sandhoff .

Editor information

Editors and Affiliations

  1. Department of Medical Biotech & Translational Medicine, University of Milan, Segrate, Milano, Italy

    Sandro Sonnino

  2. Department of Medical Biotech & Translational Medicine, University of Milan, Segrate, Milano, Italy

    Alessandro Prinetti

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Breiden, B., Sandhoff, K. (2018). Ganglioside Metabolism and Its Inherited Diseases. In: Sonnino, S., Prinetti, A. (eds) Gangliosides. Methods in Molecular Biology, vol 1804. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8552-4_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-8552-4_5

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-8551-7

  • Online ISBN: 978-1-4939-8552-4

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation