Skip to main content
PMC home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;8(1):79–100. doi: 10.1111/j.1750-3639.1998.tb00138.x

Recent Advances in the Biochemistry of Sphingolipidoses

Thomas Kolter 1, Konrad Sandhoff 1,✉
PMCID: PMC8098506  PMID: 9458169

Abstract

Glycosphingolipids are ubiquitous membrane components of eukaryotic cells. They participate in various cell recognition events and can regulate enzymes and receptors within the plasma membrane. Sphingolipidoses are due to an impaired lysosomal digestion of these substances. Glycosphingolipids are degraded by the action of exohydrolases, which are supported, in the case of glycosphingolipids with short oligosaccharide chains, by sphingolipid activator proteins. Five sphingolipid activator proteins are known so far, the GM2‐activator and the SAPs, SAP‐A to D (also called saposins). Degradation of glycosphingolipids requires endocytic membrane flow of plasma membrane derived glycosphingolipids into the lysosomes. Recent research focused on the topology of this process and on the mechanism and physiological function of sphingolipid activator proteins. Limited knowledge is available about enzymology and topology of glycosphingolipid biosynthesis. Recently, intermediates of this metabolic pathway have been identified as novel signalling molecules. Inhibition of glycosphingolipid biosynthesis has been shown to be beneficial in the animal model of Tay‐Sachs disease. Mice with disrupted genes for lysosomal hydrolases and activator proteins are useful models for known human diseases and are valuable tools for the study of glycosphingolipid metabolism, the pathogenesis of sphingolipidoses and novel therapeutic approaches.

Full Text

The Full Text of this article is available as a PDF (349.1 KB).

References

  • 1. Ballabio A, Shapiro LJ (1995) Steroid sulfatase deficiency and X‐linked ichthyosis. In: The Metabolic and Molecular Basis of Inherited Disease, Scriver C, Beaudet AL, Sly WS, Valle D, (eds.), 7th Edition, Chapter 96, pp. 2999–3022, McGraw‐Hill: New York . [Google Scholar]
  • 2. Barton NW, Furrish FS, Murray GJ, Garfield M, Brady RO (1990) Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci USA 87: 1913–1916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Bernardo K, Hurwitz R, Zenk T, Desnick RJ, Ferlinz K, Schuchman EH, Sandhoff K (1995) Purification, characterization, and biosynthesis of human acid ceramidase. J Biol Chem 270: 11098–11102. [DOI] [PubMed] [Google Scholar]
  • 4. Bielawska A, Crane HM, Liotta D, Obeid LM, Hannun YA (1993) Selectivity of ceramide‐mediated biology ‐ lack of activity of erythro‐dihydroceramide. J Biol Chem 268: 26226–26232. [PubMed] [Google Scholar]
  • 5. 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: 143–152. [DOI] [PubMed] [Google Scholar]
  • 6. Braulke T (1996) Origin of lysosomal proteins. Subcellular Biochemistry 29: 15–49. [DOI] [PubMed] [Google Scholar]
  • 7. Brooks DA (1997) Protein processing: a role in the pathophysiology of genetic disease. FEBS Lett 409: 115–120. [DOI] [PubMed] [Google Scholar]
  • 8. Buehrer BM, Bell RM (1993) Sphingosine Kinase: Properties and Cellular Function. Adv Lipid Res 26: 59–67. [PubMed] [Google Scholar]
  • 9. 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 Biochem 73: 10–18. [PubMed] [Google Scholar]
  • 10. Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, Gu J, Rosenfeld MA, Pavan WJ, Krizman DB, Nagle J, Polymeropoulos MH, Sturley SL, Loannou YA, Higgins ME, Comly M, Cooney A, Brown A, Kaneski CR, Blanchette Mackie EJ, Dwyer NK, Neufeld EB, Chang T, Liscum L, Strauss JF, Ohno K, Zeigler M, Carni R, Sokol J, Markie D, O'Neill RR, Van Diggelen OP, Elleder M, Patterson MC, Brady RO, Vanier MT, Pentchev PG, Tagle DA (1997) Niemann‐Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277: 228–231. [DOI] [PubMed] [Google Scholar]
  • 11. Chatterjee S, Gosh N, Khurana S (1992) Purification of uridine‐diphosphate‐galactose: glucosyl ceramide, (1–4 galactosyltransferase from human kidney. J Biol Chem 267: 7148–7153. [PubMed] [Google Scholar]
  • 12. Chen YQ, Rafi MA, De Gala G, Wenger DA (1993) Cloning and expression of cDNA encoding human galactocerebrosidase, the enzyme deficient in globoid cell leukodystrophy. Hum Mol Genet 2: 1841–1845. [DOI] [PubMed] [Google Scholar]
  • 13. Chen YQ, Wenger DA (1993) Galactocerebrosidase from human urine: purification and partial characterization. Biochim Biophys Acta 1170: 53–61. [DOI] [PubMed] [Google Scholar]
  • 14. Christomanou H, Aignesberg A, Linke RP (1986) Immunochemical characterization of two activator proteins stimulating enzymic sphingomyelin degradation in vitro ‐ Absence of one of them in a human Gaucher disease variant. Biol Chem Hoppe-Seyler 367: 879–890. [DOI] [PubMed] [Google Scholar]
  • 15. Cohen‐Tannoudji M, Marchand P, Akli S, Sheardown SA, Peuch JP, Kress C, Gressens P, Nassogne MC, Beccari T, Muggleton‐Harris AL, Evrard P, Stirling JL, Poenaru L, Babinet C (1995) Disruption of murine Hexa gene leads to enzymatic deficiency and to neuronal lysosomal storage, similar to that observed in Tay‐Sachs disease. Mam Genome 6: 844–849. [DOI] [PubMed] [Google Scholar]
  • 16. Conzelmann E, Sandhoff K (198384) Partial enzyme deficiencies: Residual activities and the development of neurological disorders. Dev Neurosci 6: 58–71. [DOI] [PubMed] [Google Scholar]
  • 17. D'Azzo A, Andria G, Strisciuglio P, Galjaard H (1995) Galactosialidosis. In: The Metabolic and Molecular Basis of Inherited Disease, Scriver C, Beaudet AL, Sly WS, Valle D, (eds.), 7th Edition, Chapter 91, pp. 2825–2837, McGraw‐Hill: New York . [Google Scholar]
  • 18. D'Azzo A, Hoogeveen A, Reuser AJJ, Robinson D, Galjaard H (1982) Molecular defect in combined (‐galactosidase and neuraminidase deficiency in man. Proc Natl Acad Sci USA 79: 4535–4539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Desnick RJ, Loannou YA, Eng CM (1995) (‐Galactosidase A Deficiency: Fabry Disease. In: The Metabolic and Molecular Basis of Inherited Disease, Scriver C, Beaudet AL, Sly WS, Valle D, (eds.), 7th Edition, Chapter 89, pp. 2741–2784, McGraw‐Hill: New York . [Google Scholar]
  • 20. Desnick RJ, Wang AM (1995) (‐N‐acetylgalactosaminidase deficiency: Schindler disease. In: The Metabolic and Molecular Basis of Inherited Disease, Scriver C, Beaudet AL, Sly WS, Valle D, (eds.), 7th Edition, Chapter 80, pp. 2509–2528 McGraw‐Hill: New York . [Google Scholar]
  • 21. Divecha N, Irvine RF (1995) Phospholipid signaling. Cell 80: 269–278. [DOI] [PubMed] [Google Scholar]
  • 22. Fernandes MJG, Yew S, Leclerc D, Henrissat B, Vorgias CE, Gravel RA, Hechtman P, Kaplan F (1997) Identification of candidate active site residues in lysosomal b‐hex‐osaminidase A. J Biol Chem 272: 814–820. [DOI] [PubMed] [Google Scholar]
  • 23. Fujita N, Suzuki K, Vanier MT, Popko B, Maeda N, Klein A, Henseler M, Sandhoff K, Nakayasu H, Suzuki K (1996) Targeted disruption of the mouse sphingolipid activator protein gene: a complex phenotype, including severe leukodystrophy and wide‐spread storage of multiple sphingolipids. Hum Mol Genet 5: 711–725. [DOI] [PubMed] [Google Scholar]
  • 24. Fürst W, Machleidt W, Sandhoff K (1988) The precursor of sulfatide activator protein is processed to three different proteins. Biol Chem Hoppe-Seyler 369: 317–328. [DOI] [PubMed] [Google Scholar]
  • 25. Fürst W, Sandhoff K (1992) Activator proteins and topology of lysosomal sphingolipid catabolism. Biochim Biophys Acta 1126: 1–16. [DOI] [PubMed] [Google Scholar]
  • 26. Fürst W, Schubert J, Machleidt W, Meyer EH, Sandhoff K (1990) The complete amino‐acid sequences of human ganglioside GM2 activator protein and cerebroside sulfate activator protein. Eur J Biochem 192: 709–714. [DOI] [PubMed] [Google Scholar]
  • 27. Futerman AH, Stieger B, Hubbard AL, Pagano RE (1990) Sphingomyelin synthesis in rat liver occurs predominantly at the cis and medial cisternae of the golgi apparatus. J Biol Chem 265: 8650–8657. [PubMed] [Google Scholar]
  • 28. Gahl WA, Schneider JA, Aula PP (1995) Lysosomal transport disorders: cystinosis and sialic acid storage disorders. In: The Metabolic and Molecular Basis of Inherited Disease, Scriver C, Beaudet AL, Sly WS, Valle D, (eds.), 7th Edition, Chapter 126, pp. 3763–3797, McGraw‐Hill: New York . [Google Scholar]
  • 29. Gieselmann V (1995) Lysosomal storage diseases. Biochim Biophys Acta 1270: 103–136. [DOI] [PubMed] [Google Scholar]
  • 30. Gillard BK, Harrell RG, Marcus DM (1996) Pathway of glycosphingolipid biosynthesis in SW13 cells in the presence and absence of vimentin intermediate filaments. Glycobiol 6: 33–42. [DOI] [PubMed] [Google Scholar]
  • 31. Glombitza GJ, Becker E, Kaiser HW, Sandhoff K (1997) Biosynthesis, processing, and intracellular transport of GM2 activator protein in human epidermal keratinocytes. The lysosomal targeting of the GM2 activator is independent of a mannose‐6‐phosphate signal. J Biol Chem 272: 5199–5207. [DOI] [PubMed] [Google Scholar]
  • 32. 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: 1060–1068. [DOI] [PubMed] [Google Scholar]
  • 33. Gravel RA, Clarke JTR, Kaback MM, Mahuran D, Sandhoff K, Suzuki K (1995) The GM2 Gangliosidoses. In: The Metabolic and Molecular Basis of Inherited Disease, Scriver C, Beaudet AL, Sly WS, Valle D, (eds.), 7th Edition, Chapter 92, pp. 2839–2879, McGraw‐Hill: New York . [Google Scholar]
  • 34. Griffiths GW, Hoflack B, Simons K, Mellman IS, Kornfeld S (1988) The mannose‐6‐phosphate receptor and the biogenesis of lysosomes. Cell 52: 329–341. [DOI] [PubMed] [Google Scholar]
  • 35. Hahn CN, del Pilar M, Schröder M, Vanier MT, Hara Y, Suzuki K, Suzuki K, D'Azzo A (1997) Generalized CNS disease and massive GM1‐ganglioside accumulation in mice defective in lysosomal acid beta‐galactosidase. Hum Mol Genet 6: 205–211. [DOI] [PubMed] [Google Scholar]
  • 36. Hakomori S (1981) Glycosphingolipids in cellular interactions, differentiation and oncogenesis. Annu Rev Biochem 50: 733–764. [DOI] [PubMed] [Google Scholar]
  • 37. Hannun YA (1994) The sphingomyelin cycle and the second messenger function of ceramide. J Biol Chem 269: 3125–3128. [PubMed] [Google Scholar]
  • 38. Harzer K, Paton BC, Poulos A (1989) Sphingolipid activator protein (SAP) deficiency in a 16‐week old atypical Gaucher disease patient and his fetal sibling biochemical signs of combined sphingolipidoses. Eur J Pediatr 149: 31–39. [DOI] [PubMed] [Google Scholar]
  • 39. Hassler DF, Bell RM (1993) Ceramidases: enzymology and metabolic roles. Adv Lipid Res 26: 49–57. [PubMed] [Google Scholar]
  • 40. Henseler M, Klein A, Reber M, Vanier MT, Landrieu P, Sandhoff K (1996) Analysis of a splice‐site mutation in the SAP‐precursor gene of a patient with metachromatic leukodystrophy. Am J Hum Genet 58: 65–74. [PMC free article] [PubMed] [Google Scholar]
  • 41. Hess B, Saftig P, Hartmann D, Coenen R, Lüllmann‐Rauch R, Goebel HH, Evers M, von Figura K, D'Hooge R, Nagels G, De Deyn P, Peters C, Gieselmann V (1996) Phenotype of arylsulfatase A‐deficient mice: Relationship to human metachromatic leukodystrophy. Proc Natl Acad Sci USA 93: 14821–14826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Hidari K, Kawashima I, Tai T, Inagaki F, Nagai Y, Sanai Y (1994) In vitro synthesis of disialoganglioside (GD1a) from asialo‐GM1 using sialyltransferase in rat liver golgi vesicles. Eur J Biochem 221: 603–609. [DOI] [PubMed] [Google Scholar]
  • 43. Ho MW, O'Brien JS (1971) Gaucher's disease: deficiency of ‘acid’ (‐glucosidase and reconstitution of enzyme activity in vitro. Proc Natl Acad Sci USA 68: 2810–2813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Holleran WM, Mao‐Qiang M, Gao WN, Menon GK, Elias PM, Feingold KR (1991) Sphingolipids are required for mammalian epidermal barrier function. J Clin Invest 88: 1338–1345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Holleran WM, Williams ML, Gao WN, Elias PM (1990) Serine‐palmitoyl transferase activity in cultured human keratinocytes. J Lipid Res 31: 1655–1661. [PubMed] [Google Scholar]
  • 46. Holmgren J, Lönnroth I, Mansson J‐E, Svennerholm L (1975) Interaction of cholera toxin and membrane GM1 ganglioside of small intestine. Proc Natl Acad Sci USA 72: 2520–2524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Holtschmidt H, Sandhoff K, Fürst W, Kwon H, Schnabel D, Suzuki K (1991) The organization of the gene for the human cerebroside sulfate activator protein. FEBS Lett 280: 267–270. [DOI] [PubMed] [Google Scholar]
  • 48. 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: 447–450. [DOI] [PubMed] [Google Scholar]
  • 49. Iber H, Van Echten G, Klein RA, Sandhoff K (1990) pH‐dependent changes of ganglioside biosynthesis in neuronal cell culture. Eur J Cell Biol 52: 236–240. [PubMed] [Google Scholar]
  • 50. Ichikawa S, Sakiyama H, Suzuki G, Hidari K, Hirabayashi Y (1996) Expression cloning of a cDNA for human ceramide glucosyltranferase that catalyzes the first glycosylation step of glycosphingolipid synthesis. Proc Natl Acad Sci USA 93: 4638–4643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Karlsson KA (1989) Animal glycosphingolipids as membrane attachment sites for bacteria. Annu Rev Biochem 58: 309–350. [DOI] [PubMed] [Google Scholar]
  • 52. Klein A, Henseler M, Klein C, Suzuki K, Harzer K, Sandhoff K (1994) Sphingolipid activator protein D (SAP‐D) stimulates the lysosomal degradation of ceramide in vivo. Biochem Biophys Res Commun 200: 1440–1448. [DOI] [PubMed] [Google Scholar]
  • 53. Klima H, Klein A, Van Echten G, Schwarzmann G, Suzuki K, Sandhoff K (1993) Over‐expression of a functionally active human GM2‐activator protein in Escherichia coli. Biochem J 292: 571–576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Koch J, Gärtner S, Li CM, Quintern LE, Bernardo K, Levran O, Schnabel D, Desnick RJ, Schuchman EH, Sandhoff K (1996) Molecular cloning and characterization of a full‐length complementary DNA encoding human acid ceramidase. Identification of the first molecular lesion causing Farber disease. J Biol Chem 271: 33110–33115. [DOI] [PubMed] [Google Scholar]
  • 55. Kolesnick R, Golde DW (1994) The sphingomyelin pathway in tumor necrosis factor and interleukin‐1‐signaling. Cell 77: 325–328. [DOI] [PubMed] [Google Scholar]
  • 56. Kolodny EH, Fluharty AL (1995) Metachromatic Leukodystrophy and Multiple Sulfatase Deficiency: Sulfatide Lipidosis. In: The Metabolic and Molecular Basis of Inherited Disease, Scriver C, Beaudet AL, Sly WS, Valle D, (eds.), 7th Edition, Chapter 88, pp. 2693–2739, McGraw‐Hill: New York . [Google Scholar]
  • 57. Kolter T (1997) A chemical concept for the treatment of Tay‐Sachs disease. Angew. Chem. Int. Ed. Engl. in press. [Google Scholar]
  • 58. Kolter T, Sandhoff K (1996) Inhibitors of glycosphingolipid biosynthesis. Chem Soc Rev 25: 371–381. [Google Scholar]
  • 59. Kolter T, Sandhoff K (1997) Animal models of GM2‐gangliosidoses. J Inher Metab Dis, in press. [DOI] [PubMed] [Google Scholar]
  • 60. Kornfeld S, Mellman I (1989) The biogenesis of lysosomes. Annu Rev Cell Biol 5: 483–525. [DOI] [PubMed] [Google Scholar]
  • 61. Kotani Y, Matsuda S, Wen TC, Sakanaka M, Tanaka J, Maeda N, Kondoh K, Ueno S, Sano A. (1996) A hydrophobic peptide comprising 18 amino acid residues of the prosaposin sequence has neurotrophic activity in vitro and in vivo. J Neurochem 66: 2197–2200. [DOI] [PubMed] [Google Scholar]
  • 62. Kretz KA, Carson GS, Morimoto S, Kishimoto Y, Fluharty AL, O'Brien JS (1990) Characterization of a mutation in a family with saposin B deficiency: a glycosylation site defect. Proc Natl Acad Sci USA 87: 2541–2544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Kytzia HJ, Hinrichs U, Maire I, Suzuki K, Sandhoff K (1983) Variant of GM2‐gangliosidosis with hexosaminidase A having a severely changed substrate specificity. EMBO J 2: 1201–1205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Kytzia HJ, Sandhoff K (1985) Evidence for two different active sites on human hexosaminidase ‐ Interaction of GM2 activator protein with hexosaminidase A. J Biol Chem 260: 7568–7572. [PubMed] [Google Scholar]
  • 65. Lannert H, Bünning C, Jeckel D, Wieland FT (1994) Lactosylceramide is synthesized in the lumen of the Golgi apparatus. FEBS Lett 342: 91–96. [DOI] [PubMed] [Google Scholar]
  • 66. Ledeen RW, Wu G (1992) Ganglioside function in the neuron. Trends Glycosci. Glycotechnol 4: 174–187. [Google Scholar]
  • 67. Leinekugel P, Michel S, Conzelmann E, Sandhoff K (1992) Quantitative correlation between the residual activity of (‐hexosaminidase A and arylsulfatase A and the severity of the resulting lysosomal storage disease. Hum Genet 88: 513–523. [DOI] [PubMed] [Google Scholar]
  • 68. Levade T, Moser HW, Fensom AH, Harzer K, Moser AB, Salvayre R (1994) Neurodegenerative course in ceramidase deficiency (Farber disease) correlates with the residual lysosomal ceramide turnover in cultured living patient cells. J Neurol Sci 134: 108–114. [DOI] [PubMed] [Google Scholar]
  • 69. Li SC, Sonnino S, Tettamanti G, Li YT (1988) Characterization of a nonspecific activator protein for the enzymatic hydrolysis of glycolipids. J Biol Chem 263: 6588–6591. [PubMed] [Google Scholar]
  • 70. Liu Y, Hoffmann A, Grinberg A, Westphal H, McDonald MP, Miller KM, Crawley JN, Sandhoff K, Suzuki K, Praia RL (1997) Mouse model of GM2 activator deficiency manifests cerebellar ganglioside storage and motor impairment. Proc Natl Acad Sci USA 94: 8138–8143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71. Loftus SK, Morris JA, Carstea ED, Gu JZ, Cummings C, Brown A, Ellison J, Ohno K, Rosenfeld MA, Tagle DA, Pentchev PG, Pavan VJ (1997) Murine model of Niemann‐Pick C disease: mutation in a cholesterol homeostasis gene. Science 277: 232–234. [DOI] [PubMed] [Google Scholar]
  • 72. Lüllmann‐Rauch R (1974) Lipidosis‐like alterations in spinal cord and cerebellar cortex of rats treated with tricyclic antidepressants or neuroleptics. Acta Neuropathol 29: 237–249. [DOI] [PubMed] [Google Scholar]
  • 73. Luzi P, Rafi MA, Wenger DA (1995) Structure and organization of the human galactocerebrosidase (GALC) gene. Genomics 26: 407–409. [DOI] [PubMed] [Google Scholar]
  • 74. Maccioni HJF, Fritz VR, Maxzud MK, Daniotti JL, Martina JA (1996) Compartmental organization of ganglioside synthesis in the Golgi complex. Biocell 20: 279–286. [PubMed] [Google Scholar]
  • 75. Mandon E, Ehses I, Rother J, Van Echten G, Sandhoff K (1992) Subcellular localization and membrane topology of serine palmitoyltransferase, 3‐dehydrosphinganine reductase and sphinganine N‐acyltransferase in mouse liver. J Biol Chem 267: 11144–11148. [PubMed] [Google Scholar]
  • 76. Markwell MAK, Svennerholm L, Paulson JC (1981) Specific gangliosides function as host cell receptors for Sendai virus. Proc Natl Acad Sci USA 78: 5406–5410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77. Mehl E, Jatzkewitz H (1964) Eine Cerebrosidsulfatase aus Schweineniere. Hoppe-Seyler's Z Physiol Chem 339: 260–276. [PubMed] [Google Scholar]
  • 78. Meier EM, Schwarzmann G, Fürst W, Sandhoff K (1991) The human GM2 activator protein: a substrate specific cofactor of hexosaminidase A. J Biol Chem 266: 1879–1887. [PubMed] [Google Scholar]
  • 79. Mellman I (1996) Endocytosis and molecular sorting. Annu Rev Cell Dev Biol 12: 575–625. [DOI] [PubMed] [Google Scholar]
  • 80. Merrill AH Jr, Sweeley CC (1996) Sphingolipids: metabolism and cell signalling. In: Biochemistry of Lipids, Lipoproteins and Membranes, Vance DE, Vance JE, (eds.), pp. 309–339, Elsevier, Amsterdam . [Google Scholar]
  • 81. Meyer zu Heringdorf D, Van Koppen CJ, Jakobs KH (1997) Molecular diversity of sphingolipid signalling. FEBS Lett 410: 34–38. [DOI] [PubMed] [Google Scholar]
  • 82. Michel C, Van Echten‐Deckert G, Rother J, Sandhoff K, Wang E, Merrill, Jr., AH (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: 22432–22437. [DOI] [PubMed] [Google Scholar]
  • 83. Miyataki T, Suzuki K (1972) Globoid cell leukodystrophy: Additional deficiency of psychosine galactosidase. Biochem Biophys Res Commun 48: 539–543. [DOI] [PubMed] [Google Scholar]
  • 84. Munford RS, Sheppard PO, O'Hara PJ (1995) Saposin‐like proteins (SAPLIP) carry out diverse functions on a common backbone structure. J Lipid Res 36: 1653–1663. [PubMed] [Google Scholar]
  • 85. Nagai Y, Iwamori M (1995) Cellular Biology of Gangliosides. In: Biology of the Sialic Acids (Rosenberg A, ed), Plenum Press, New York , 197–241. [Google Scholar]
  • 86. Nakano T, Sandhoff K, Stumper J, Christomanou H, Suzuki K (1989) Structure of full‐length cDNA coding for sulfatide activator, a co‐b‐glucosidase and two other homologous proteins: Two alternate forms of the sulfatide activator. J Biochem 105: 152–154. [DOI] [PubMed] [Google Scholar]
  • 87. Neufeld EF (1991) Lysosomal storage diseases. Annu Rev Biochem 60: 257–280. [DOI] [PubMed] [Google Scholar]
  • 88. Neufeld EF, Muenzer J (1995) The mucopolysaccharidoses. In: The Metabolic and Molecular Basis of Inherited Disease, Scriver C, Beaudet AL, Sly WS, Valle D, (eds.), 7th Edition, Chapter 78, pp. 2465–2494, McGraw‐Hill: New York . [Google Scholar]
  • 89. Nilsson O, Svennerholm L (1982) Accumulation of glucosylceramide and glucosylsphingosine (psychosine) in cerebrum and cerebellum in infantile and juvenile Gaucher disease. J Neurochem 39: 709–718. [DOI] [PubMed] [Google Scholar]
  • 90. O'Brien JS, Carson GS, Seo H‐C, Hiraiwa M, Weiler S, Tomich JM, Barranger JA, Kahn M, Azuma N, Kishimoto Y (1995) Identification of the neurotrophic sequence of prosaposin. FASEB J 9: 681–685. [DOI] [PubMed] [Google Scholar]
  • 91. O'Brien JS, Kretz KA, Dewji N, Wenger DA, Esch F, Fluharty AL (1988) Coding of two sphingolipid activator proteins (SAP‐1 and SAP‐2) by same genetic locus. Science 241: 1098–1101. [DOI] [PubMed] [Google Scholar]
  • 92. Paul P, Kamisaka Y, Marks DL, Pagano RE (1996) Purification and characterization of UDP‐glucose:ceramide glucosyltransferase from rat liver Golgi membranes. J Biol Chem 271: 2287–2293. [DOI] [PubMed] [Google Scholar]
  • 93. Penzien JM, Kappler JM, Herschkowitz N, Schuknecht B, Leinekugel P, Propping P, Tonnessen T, Lou H, Moser H, Ziers S, Conzelmann E, Gieselmann V (1993) Compound heterozygosity for metachromatic leukodystrophy and arylsulfatase A pseudodeficiency alleles is not associated with progressive neurological disease. Am J Hum Genet 52: 557–564. [PMC free article] [PubMed] [Google Scholar]
  • 94. Phaneuf D, Wakamatsu N, Huang JQ, Borowski A, Peterson A, Fortunato SR, Ritter G, Igdoura SA, Morales CR, Benoit G, Akerman BR, Leclerc D, Hanai N, Marth JD, Trasler JM, Gravel RA (1996) Dramatically different phenotypes in mouse models of human Tay‐Sachs and Sandhoff disease. Hum Mol Genet 5: 1–14. [DOI] [PubMed] [Google Scholar]
  • 95. Phillips ML, Nudelman E, Gaeta FCA, Perez M, Singhal AK, Hakomori S, Paulson JC (1990) ELAM 1 mediates cell adhesion by recognition of a carbohydrate ligand, Sialyl‐Lex. Science 250: 1130–1132. [DOI] [PubMed] [Google Scholar]
  • 96. Pisoni RL, Thoene, JG (1991) The transport systems of mammalian lysosomes. Biochim Biophys Acta 1071: 351–373. [DOI] [PubMed] [Google Scholar]
  • 97. Platt FM, Neises GR, Karlsson GB, Dwek RA, Butters TD (1994) N‐butyldeoxynojirimycin inhibits glycolipid biosynthesis but does not affect N‐linked oligosaccharide processing. J Biol Chem 269: 27108–27114. [PubMed] [Google Scholar]
  • 98. Platt FM, Neises GR, Reinkensmeier G, Townsend MJ, Perry VH, Praia RL, Winchester B, Dwek RA, Butters TD (1997). Prevention of lysosomal storage in Tay‐Sachs mice treated with N‐butyldeoxynojirimycin. Science 276: 428–431. [DOI] [PubMed] [Google Scholar]
  • 99. Platt FM, Reinkensmeier G, Dwek RA, Butters TD (1997) Extensive glycosphingolipid depletion in the liver and lymphoid organs of mice treated with N‐butyldeoxynojirimycin. J Biol Chem 272: 19365–19372. [DOI] [PubMed] [Google Scholar]
  • 100. Quintern LE, Schuchmann EH, Levran O, Suchi M, Ferlinz K, Reinke H, Sandhoff K, Desnick RJ (1989) Isolation of cDNA clones encoding human acid sphingomyelinase: Occurence of alternatively processed transcripts. EMBO J 8: 2469–2473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101. 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: 323–336. [DOI] [PubMed] [Google Scholar]
  • 102. Purpura DP, Suzuki K (1976) Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage disease. Brain Res 116: 1–21. [DOI] [PubMed] [Google Scholar]
  • 103. Rafi MA, De Gala G, Zhang X, Wenger DA (1993) Mutational analysis in a patient with a variant form of Gaucher disease caused by SAP‐2 deficiency. Somat Cell Mol Genet 19: 1–7. [DOI] [PubMed] [Google Scholar]
  • 104. Rafi MA, Zhang XL, De Gala G, Wenger DA (1990) Detection of a point mutation in sphingolipid activator protein 1 mRNA in patients with a variant form of metachromatic leukodystrophy. Biochem Biophys Res Commun 166: 1017–1023. [DOI] [PubMed] [Google Scholar]
  • 105. Renfrew CA, Hubbard AL (1991) Degradation of epidermal growth factor receptor in rat liver. J Biol Chem 266: 21265–21273. [PubMed] [Google Scholar]
  • 106. Robinson MS, Watts C, Zerial M (1996) Membrane dynamics in endocytosis. Cell 84: 13–21. [DOI] [PubMed] [Google Scholar]
  • 107. Rommerskirch W, von Figura K (1992) Multiple sulfatase deficiency: catalytically inactive sulfatases are expressed from retrovirally introduced cDNAs. Proc Natl Acad Sci USA 89: 2561–2565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108. 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: 14–20. [DOI] [PubMed] [Google Scholar]
  • 109. Sakai N, Inui K, Fujii N, Fukushima H, Nishimoto J, Yanagihara I, Isegawa Y, Iwamatsu A, Okada S (1994) Krabbe disease: Isolation and characterization of a full‐length cDNA for human galactocerebrosidase. Biochem Biophys Res Commun 198: 485–491. [DOI] [PubMed] [Google Scholar]
  • 110. Sakai N, Inui K, Tatsumi N, Fukushima H, Nishigaki T, Taniike M, Nishimoto J, Tsukamoto H, Yanagihara I, Ozono K, Okada S (1996.) Molecular cloning and expression of cDNA for murine galactocerebrosidase and mutation analysis of the twitcher mouse, a model of Krabbe's disease. J Neurochem 66: 1118–1124. [DOI] [PubMed] [Google Scholar]
  • 111. Sandhoff K, Conzelmann E, Neufeld E, Kaback MM, Suzuki K (1989) The GM2 gangliosidoses. In: The Metabolic Basis of Inherited Disease, Scriver C, Beaudet AL, Sly WS, Valle D, (eds.), 6th Edition, Chapter 72, pp. 1807–1839, McGraw‐Hill: New York . [Google Scholar]
  • 112. Sandhoff K, Harzer K, Fürst W (1995) Sphingolipid Activator Proteins. In: The Metabolic and Molecular Basis of Inherited Disease, Scriver C, Beaudet AL, Sly WS, Valle D, (eds.), 7th Edition, Chapter 76, pp. 2427–2441, McGraw Hill: New York . [Google Scholar]
  • 113. Sandhoff K, Kolter T (1995) Glykolipide der Zelloberfläche ‐ Biochemie ihres Abbaus. Naturwissenschaften 82: 403–413. [PubMed] [Google Scholar]
  • 114. Sandhoff K, Kolter T (1996) Topology of glycosphingolipid degradation. Trends Cell Biol 6: 98–103. [DOI] [PubMed] [Google Scholar]
  • 115. Sango K, McDonald MR Crawley JN, Mack ML, Tifft CJ, Skop E, Starr CM, Hoffmann A, Sandhoff K, Suzuki K, Proia RL (1996) Mice lacking both subunits of lysosomal (‐hexosaminidase display gangliosidosis and mucopolysaccharidosis. Nature Genet 14: 348–352. [DOI] [PubMed] [Google Scholar]
  • 116. Sango K, Yamanaka S, Hoffmann A, Okuda Y, Grinberg A, Westphal H, McDonald MP, Crawley JN, Sandhoff K, Suzuki K, Proia RL (1995) Mouse models of Tay‐Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism. Nature Genet 11: 170–176. [DOI] [PubMed] [Google Scholar]
  • 117. Santana P, Pena LA, Haimovitz‐Friedman A, Martin S, Green D, McLoughlin M, Cordon‐Cardo C, Schuchman EH, Fuks Z, Kolesnick R (1996) Acid sphingomyelinase‐deficient human lymphoblasts and mice are defective in radiation‐induced apoptosis. Cell 86: 189–199. [DOI] [PubMed] [Google Scholar]
  • 118. Schepers U, Glombitza GJ, Lemm T, Hoffmann A, Chabàs A, Ozand P, Sandhoff K (1996) Molecular analysis of a GM2‐activator deficiency in two patients with GM2‐gan‐gliosidosis AB variant. Am J Hum Genet 59: 1048–1056. [PMC free article] [PubMed] [Google Scholar]
  • 119. Schlote W, Harzer K, Christomanou H, Paton BC, Kustermann‐Kuhn B, Schmid B, Seeger J, Beudt U, Schuster I, Langenbeck U (1991) Sphingolipid activator protein 1 deficiency in metachromatic leucodystrophy with normal arylsulphatase A activity ‐ A clinical, morphological, biochemical, and immunological study. Eur J Pediatr 150: 584–591. [DOI] [PubMed] [Google Scholar]
  • 120. Schmidt B, Selmer T, Lngendoh A, von Figura K (1995) A novel amino acid modification in sulfatases that is defective in multiple sulfatase deficiency. Cell 82: 271–278. [DOI] [PubMed] [Google Scholar]
  • 121. Schnabel D, Schröder M, Fürst W, Klein A, Hurwitz R, Zenk T, Weber J, Harzer K, Paton BC, Poulos A, Suzuki K, Sandhoff K (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: 3312–3315. [PubMed] [Google Scholar]
  • 122. Schnabel D, Schröder M, Sandhoff K (1991) Mutation in the sphingolipid activator protein 2 in a patient with a variant of Gaucher disease. FEBS Lett 284: 57–59. [DOI] [PubMed] [Google Scholar]
  • 123. Schröder M, Schnabel D, Hurwitz R, Young E, Suzuki K, Sandhoff K (1993). Molecular genetics of GM2 gangliosidosis AB variant: a novel mutation and expression in BHK cells. Hum Genet 92: 437–440. [DOI] [PubMed] [Google Scholar]
  • 124. Schröder M, Schnabel D, Suzuki K, Sandhoff K (1991) A mutation in the gene of a glycolipid‐binding protein (GM2 activator) that causes GM2‐gangliosidosis variant AB. FEBS Lett 290: 1–3. [DOI] [PubMed] [Google Scholar]
  • 125. Schuchman EH, Levran O, Peireira LV, Desnick RJ (1992) Structural organization and complete nucleotide sequence of the gene encoding human acid sphingomyelinase (SMPD1). Genomics 12: 197–205. [DOI] [PubMed] [Google Scholar]
  • 126. Schulte S, Stoffel W (1993) Ceramide UDPgalactosyltransferase from myelinating rat brain: purification, cloning, and expression. Proc Natl Acad Sci USA 90: 10265–10269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 127. Spence MW (1993) Sphingomyelinases. Adv Lipid Res 26: 3–23. [PubMed] [Google Scholar]
  • 128. Spiegel S, Foster D, Kolesnick R (1996) Signal transduction through lipid second messengers. Curr Opin Cell Biol 8: 159–167. [DOI] [PubMed] [Google Scholar]
  • 129. Stults CLM, Sweeley CC, Macher BA (1989) Glycosphingolipids: structure, biological source, and properties. Methods Enzymol 179: 167–214. [DOI] [PubMed] [Google Scholar]
  • 130. Suzuki K (1994) Genetic disorders of lipid, glycoprotein, and mucopolysaccharide metabolism. In: Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, Siegel GJ, Agranoff BW, Albers RW, Molinoff PB, (eds.), 5th Edition, Chapter 38, pp. 793–812, Raven Press: New York . [Google Scholar]
  • 131. Suzuki K, Chen GC (1968) GM1‐gangliosidosis (generalized gangliosidosis). Morphology and chemical pathology. Pathol Europ 3: 389–408. [PubMed] [Google Scholar]
  • 132. Suzuki K, Vanier MT (1991) Biochemical and molecular aspects of late‐onset GM2‐gangliosidosis: B1 variant as a prototype. Dev Neurosci 13: 288–294. [DOI] [PubMed] [Google Scholar]
  • 133. Svennerholm L (1963) Chromatographic separation of human brain gangliosides. J Neurochem 10: 613–623. [DOI] [PubMed] [Google Scholar]
  • 134. Svennerholm L, Asbury AK, Reisfeld RA., Sandhoff K, Tettamanti G, Toffano G (1994) Proceedings of Nobel Symposium 83. Biological function of gangliosides. Progr Brain Res 101: 1–404. [Google Scholar]
  • 135. Taniike M, Yamanaka S, Proia RL, Langaman C, Bonc‐Turentine T, Suzuki K (1995) Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay‐Sachs disease. Acta Neuropathol (Berl) 89: 296–304. [DOI] [PubMed] [Google Scholar]
  • 136. Testi R (1996) Sphingomyelin breakdown and cell fete. Trends Biochem Sci 21: 468–471. [DOI] [PubMed] [Google Scholar]
  • 137. Toda KI, Kobayashi T, Goto I, Ohno K, Eto Y, Inui K, Okada S (1990) Lysosulfetide (sulfogalactosylsphingosine) accumulation in tissues from patients with metachromatic leukodystrophy. J Neurochem 55: 1585–1591. [DOI] [PubMed] [Google Scholar]
  • 138. Tsuji S (1996) Molecular cloning and functional analysis of sialyltransferases. J Biochem 120: 1–13. [DOI] [PubMed] [Google Scholar]
  • 139. Van Deurs B, Holm PK, Kayser L, Sandvig K, Hansen SH (1993) Multivesicular bodies in HEp‐2 cells are maturing endosomes. Eur J Cell Biol 61: 208–224. [PubMed] [Google Scholar]
  • 140. Van Echten G, Sandhoff K (1989) Modulation of ganglioside biosynthesis in primary cultured neurons. J Neurochem 52: 207–214. [DOI] [PubMed] [Google Scholar]
  • 141. Van Echten G, Sandhoff K (1993) Ganglioside metabolism. J Biol Chem 268: 5341–5344. [PubMed] [Google Scholar]
  • 142. Van Helvoort A, Van Meer G (1995) Intracellular lipid heterogeneity caused by topology of synthesis and specificity in transport. Example: sphingolipids. FEBS Lett 369: 18–21. [DOI] [PubMed] [Google Scholar]
  • 143. Van Veldhoven PP, Mannaerts GP (1993) Sphingosinephosphate lyase. Adv Lipid Res 26: 69–98. [PubMed] [Google Scholar]
  • 144. Verma IM, Somia N (1997) Gene therapy ‐ promises, problems and prospects. Nature 389: 239–242. [DOI] [PubMed] [Google Scholar]
  • 145. Vielhaber G, Hurwitz R, Sandhoff K (1997) Biosynthesis, processing, and targeting of sphingolipid activator protein (SAP) precursor in cultured human fibroblasts. Mannose 6‐phosphate receptor‐independent endocytosis of SAP precursor. J Biol Chem 272: 32438–32446. [DOI] [PubMed] [Google Scholar]
  • 146. von Figura K, Hasilik A (1986) Lysosomal enzymes and their receptors. Annu Rev Biochem 55: 167–193. [DOI] [PubMed] [Google Scholar]
  • 147. Walz G, Aruffo A, Kolanus W, Bevilacqua M, Seed B (1990) Recognition by ELAM‐1 of the sialyl‐Lex determinant on myeloid and tumor cells. Science 250: 1132–1135. [DOI] [PubMed] [Google Scholar]
  • 148. Wertz PW, Miethke MC, Long SA, Strauss JS, Downing DT (1985) The composition of ceramides from human stratum corneum and from comedones. J Invest Dermatol 84: 410–412. [DOI] [PubMed] [Google Scholar]
  • 149. Wiegandt H (1985) Gangliosides. In: New Comprehensive Biochemistry 10, Neuberger A, Van Deenen LLM, (eds.), pp. 199–260, Elsevier Science Publishers: Amsterdam . [Google Scholar]
  • 150. Yamanaka S, Johnson MD, Grinberg A, Westphal H, Crawley JN, Taniike M, Suzuki K, Praia RL (1994) Targeted disruption of the Hexa gene results in mice with biochemical and pathologic features of Tay‐Sachs disease. Proc Natl Acad Sci USA 91: 9975–9979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 151. Yatomi Y, Ruan FQ, Hakomori S, Igarashi S (1995) Sphingosine‐1‐phosphate: a platelet‐activating sphingolipid released from agonist‐stimulated human platelets. Blood 86: 193–202. [PubMed] [Google Scholar]
  • 152. Zhang XL, Rafi MA, De Gala G, Wenger DA (1990) Insertion in the mRNA of a metachromatic leukodystrophy patient with sphingolipid activator protein‐1 deficiency. Proc Natl Acad Sci USA 87: 1426–1430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 153. Zhang XL, Rafi MA, De Gala G, Wenger DA (1991) The mechanism for a 33‐nucleotide insertion in mRNA causing sphingolipid activator protein (SAP‐1)‐deficient metachromatic leukodystrophy Hum Genet 87: 211–221. [DOI] [PubMed] [Google Scholar]
  • 154. Zhou XY, Morreau H, Rottier R, Davis D, Bonten E, Gillemans N, Wenger D, Grosveld FG, Doherty P, Suzuki K, Grosveld GC, D'Azzo A (1995) Mouse model for the lysosomal disorder galactosialidosis and correction of the phenotype with over‐expressing erythroid precursor cells. Genes Dev 9: 2623–2634. [DOI] [PubMed] [Google Scholar]
  • 155. Zumbansen M, Stoffel W (1997) Tumor necrosis factor alpha activates NF‐kappa ‐B in acid sphingomyelinase‐deficient mouse embryonic fibroblasts. J Biol Chem 272: 10904–10909. [DOI] [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES