1932

Abstract

Glycosphingolipids are cell-type-specific components of the outer leaflet of mammalian plasma membranes. Gangliosides, sialic acid–containing glycosphingolipids, are especially enriched on neuronal surfaces. As amphi-philic molecules, they comprise a hydrophilic oligosaccharide chain attached to a hydrophobic membrane anchor, ceramide. Whereas glycosphingolipid formation is catalyzed by membrane-bound enzymes along the secretory pathway, degradation takes place at the surface of intralysosomal vesicles of late endosomes and lysosomes catalyzed in a stepwise fashion by soluble hydrolases and assisted by small lipid-binding glycoproteins. Inherited defects of lysosomal hydrolases or lipid-binding proteins cause the accumulation of undegradable material in lysosomal storage diseases (GM1 and GM2 gangliosidosis; Fabry, Gaucher, and Krabbe diseases; and metachromatic leukodystrophy). The catabolic processes are strongly modified by the lipid composition of the substrate-carrying membranes, and the pathological accumulation of primary storage compounds can trigger an accumulation of secondary storage compounds (e.g., small glycosphingolipids and cholesterol in Niemann-Pick disease).

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2019-06-20
2024-04-17
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Literature Cited

  1. 1. 
    Thudichum JLW. 1884. A Treatise on the Chemical Constitution of the Brain London: Bailliere, Tindall and Cox
  2. 2. 
    Rahmann H. 1983. Functional meaning of neuronal gangliosides for the process of thermal adaptation in vertebrates. J. Therm. Biol. 8:404–7
    [Google Scholar]
  3. 3. 
    Wiegandt H. 1995. The chemical constitution of gangliosides of the vertebrate nervous system. Behav. Brain Res. 66:85–97
    [Google Scholar]
  4. 4. 
    Sandhoff R, Sandhoff K 2018. Emerging concepts of ganglioside metabolism. FEBS Lett 592(23):3835–64
    [Google Scholar]
  5. 5. 
    Kracun I, Rosner H, Drnovsek V, Vukelic Z, Cosovic C et al. 1992. Gangliosides in the human brain development and aging. Neurochem. Int. 20:421–31
    [Google Scholar]
  6. 6. 
    Klenk E. 1942. Über die Ganglioside, eine neue Gruppe von zuckerhaltigen Gehirnlipoiden. Hoppe-Seyler's Z. Physiol. Chem. 273:76–86
    [Google Scholar]
  7. 7. 
    Kuhn R, Wiegandt H 1963. Die Konstitution der Ganglio-N-tetraose und des Gangliosids GI. Chem. Ber. 96:866–80
    [Google Scholar]
  8. 8. 
    Jatzkewitz H, Sandhoff K 1963. On a biochemically special form of infantile amaurotic idiocy. Biochim. Biophys. Acta 70:354–56
    [Google Scholar]
  9. 9. 
    Sandhoff K, Harzer K, Wässle W, Jatzkewitz H 1971. Enzyme alterations and lipid storage in three variants of Tay-Sachs disease. J. Neurochem. 18:2469–89
    [Google Scholar]
  10. 10. 
    Jennemann R, Sandhoff R, Wang S, Kiss E, Gretz N et al. 2005. Cell-specific deletion of glucosylceramide synthase in brain leads to severe neural defects after birth. PNAS 102:12459–64
    [Google Scholar]
  11. 11. 
    Harzer K, Jatzkewitz H, Sandhoff K 1969. Incorporation of labelled glucose into the individual major gangliosides of the brain of young rats. J. Neurochem. 16:1279–82
    [Google Scholar]
  12. 12. 
    Russo D, Della Ragione F, Rizzo R, Sugiyama E, Scalabri F et al. 2018. Glycosphingolipid metabolic reprogramming drives neural differentiation. EMBO J 37:e97674
    [Google Scholar]
  13. 13. 
    Kolter T, Sandhoff K 1999. Sphingolipids—their metabolic pathways and the pathobiochemistry of neurodegenerative diseases. Angew. Chem. Int. Ed. Engl. 38:1532–68
    [Google Scholar]
  14. 14. 
    de Duve C, Wattiaux R 1966. Functions of lysosomes. Annu. Rev. Physiol. 28:435–92
    [Google Scholar]
  15. 15. 
    Hers HG. 1965. Inborn lysosomal diseases. Gastroenterology 48:625–33
    [Google Scholar]
  16. 16. 
    Ballabio A, Gieselmann V 2009. Lysosomal disorders: from storage to cellular damage. Biochim. Biophys. Acta 1793:684–96
    [Google Scholar]
  17. 17. 
    Smutova V, Albohy A, Pan X, Korchagina E, Miyagi T et al. 2014. Structural basis for substrate specificity of mammalian neuraminidases. PLOS ONE 9:e106320
    [Google Scholar]
  18. 18. 
    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
    [Google Scholar]
  19. 19. 
    Fürst W, Sandhoff K 1992. Activator proteins and topology of lysosomal sphingolipid catabolism. Biochim. Biophys. Acta 1126:1–16
    [Google Scholar]
  20. 20. 
    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. 47:1005–14
    [Google Scholar]
  21. 21. 
    Henning R, Stoffel W 1973. Glycosphingolipids in lysosomal membranes. Hoppe-Seyler's Z. Physiol. Chem. 354:760–70
    [Google Scholar]
  22. 22. 
    Eskelinen E-L, Tanaka Y, Saftig P 2003. At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol 13:137–45
    [Google Scholar]
  23. 23. 
    Burkhardt JK, Hüttler S, Klein A, Möbius W, Habermann A et al. 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. 73:10–18
    [Google Scholar]
  24. 24. 
    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
    [Google Scholar]
  25. 25. 
    Bradová V, Smíd 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. 92:143–52
    [Google Scholar]
  26. 26. 
    Harzer K, Paton BC, Poulos A, Kustermann-Kuhn B, Roggendorf W et al. 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. 149:31–39
    [Google Scholar]
  27. 27. 
    Schnabel D, Schröder M, Fürst W, Klein A, Hurwitz R 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. 267:3312–15
    [Google Scholar]
  28. 28. 
    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. 19:307–16
    [Google Scholar]
  29. 29. 
    Gallala HD, Breiden B, Sandhoff K 2011. Regulation of the NPC2 protein-mediated cholesterol trafficking by membrane lipids. J. Neurochem. 116:702–7
    [Google Scholar]
  30. 30. 
    Kobayashi T, Beuchat MH, Lindsay M, Frias S, Palmiter RD et al. 1999. Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport. Nat. Cell Biol. 1:113–18
    [Google Scholar]
  31. 31. 
    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. 55:2606–19
    [Google Scholar]
  32. 32. 
    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. 273:30271–78
    [Google Scholar]
  33. 33. 
    Kölzer M, Werth N, Sandhoff K 2004. Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine. FEBS Lett 559:96–98
    [Google Scholar]
  34. 34. 
    Hurwitz R, Ferlinz K, Sandhoff K 1994. The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts. Biol. Chem. Hoppe-Seyler 375:447–50
    [Google Scholar]
  35. 35. 
    Elojeimy S, Holman DH, Liu X, El-Zawahry A, Villani M et al. 2006. New insights on the use of desipramine as an inhibitor for acid ceramidase. FEBS Lett 580:4751–56
    [Google Scholar]
  36. 36. 
    Lüllmann H, Lüllmann-Rauch R, Wassermann O 1978. Lipidosis induced by amphiphilic cationic drugs. Biochem. Pharmacol. 27:1103–8
    [Google Scholar]
  37. 37. 
    Suzuki K, Chen GC 1968. GM1-gangliosidosis (generalized gangliosidosis). Morphology and chemical pathology. Pathol. Eur. 3:389–408
    [Google Scholar]
  38. 38. 
    Terry RD, Weiss M 1963. Studies in Tay-Sachs disease: II. Ultrastructure of the cerebrum. J. Neuropathol. Exp. Neurol. 22:18–55
    [Google Scholar]
  39. 39. 
    Lee RE. 1968. The fine structure of the cerebroside occurring in Gaucher's disease. PNAS 61:484–89
    [Google Scholar]
  40. 40. 
    van Meer G, Voelker DR, Feigenson GW 2008. Membrane lipids: where they are and how they behave. Nat. Rev. Mol. Cell Biol. 9:112–24
    [Google Scholar]
  41. 41. 
    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. 51:1747–60
    [Google Scholar]
  42. 42. 
    Anheuser S, Breiden B, Schwarzmann G, Sandhoff K 2015. Membrane lipids regulate ganglioside GM2 catabolism and GM2 activator protein activity. J. Lipid Res. 56:1747–61
    [Google Scholar]
  43. 43. 
    Vanier MT. 2015. Complex lipid trafficking in Niemann-Pick disease type C. J. Inherit. Metab. Dis. 38:187–99
    [Google Scholar]
  44. 44. 
    Wang ML, Motamed M, Infante RE, Abi-Mosleh L, Kwon HJ et al. 2010. Identification of surface residues on Niemann-Pick C2 essential for hydrophobic handoff of cholesterol to NPC1 in lysosomes. Cell Metab 12:166–73
    [Google Scholar]
  45. 45. 
    Vanier MT, Millat G 2003. Niemann-Pick disease type C. Clin. Genet. 64:269–81
    [Google Scholar]
  46. 46. 
    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. 58:563–77
    [Google Scholar]
  47. 47. 
    Vanier M. 1983. Biochemical studies in Niemann-Pick disease: I. Major sphingolipids of liver and spleen. Biochim. Biophys. Acta 750:178–84
    [Google Scholar]
  48. 48. 
    Locatelli-Hoops S, Remmel N, Klingenstein R, Breiden B, Rossocha M et al. 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. 281:32451–60
    [Google Scholar]
  49. 49. 
    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 274:3405–20
    [Google Scholar]
  50. 50. 
    Sandhoff K. 2013. Metabolic and cellular bases of sphingolipidoses. Biochem. Soc. Trans. 41:1562–68
    [Google Scholar]
  51. 51. 
    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. 275:35814–19
    [Google Scholar]
  52. 52. 
    Sango K, Yamanaka S, Hoffmann A, Okuda Y, Grinberg A et al. 1995. Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism. Nat. Genet. 11:170–76
    [Google Scholar]
  53. 53. 
    Seyrantepe V, Demir SA, Timur ZK, Von Gerichten J, Marsching C et al. 2017. Murine sialidase Neu3 facilitates GM2 degradation and bypass in mouse model of Tay-Sachs disease. Exp. Neurol. 299:26–41
    [Google Scholar]
  54. 54. 
    Kolter T, Sandhoff K 2006. Sphingolipid metabolism diseases. Biochim. Biophys. Acta 1758:2057–79
    [Google Scholar]
  55. 55. 
    Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE et al., eds. 2001. Part 16, Lysosomal disorders. The Online Metabolic and Molecular Bases of Inherited Disease New York: McGraw-Hill Education
    [Google Scholar]
  56. 56. 
    Sandhoff K, Harzer K 2013. Gangliosides and gangliosidoses. Principles of molecular and metabolic pathogenesis. J. Neurosci. 33:10195–208
    [Google Scholar]
  57. 57. 
    Brunetti-Pierri N, Scaglia F 2008. GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol. Genet. Metab. 94:391–96
    [Google Scholar]
  58. 58. 
    Morreau H, Galjart NJ, Gillemans N, Willemsen R, van der Horst GT, d'Azzo A 1989. Alternative splicing of β-galactosidase mRNA generates the classic lysosomal enzyme and a β-galactosidase-related protein. J. Biol. Chem. 264:20655–63
    [Google Scholar]
  59. 59. 
    d'Azzo A, Bonten E 2010. Molecular mechanisms of pathogenesis in a glycosphingolipid and a glycoprotein storage disease. Biochem. Soc. Trans. 38:1453–57
    [Google Scholar]
  60. 60. 
    Pshezhetsky AV, Ashmarina M 2001. Lysosomal multienzyme complex: biochemistry, genetics, and molecular pathophysiology. Prog. Nucleic Acid. Res. Mol. Biol. 69:81–114
    [Google Scholar]
  61. 61. 
    Sandhoff K, Jatzkewitz H, Peters G 1969. Die infantile amaurotische Idiotie und verwandte Formen als Gangliosid-Specherkrankheiten. Naturwissenschaften 56:356–62
    [Google Scholar]
  62. 62. 
    Suzuki Y, Oshima A, Nanba E 2001. β-Galactosisdase deficiency (β-galactosidosis): GM1 gangliosidosis and Morquio B disease. The Metabolic and Molecular Bases of Inherited Diseases CR Scriver, AL Beaudet, WS Sly, D Valle 3775–809 New York: McGraw-Hill
    [Google Scholar]
  63. 63. 
    Caciotti A, Garman SC, Rivera-Colon Y, Procopio E, Catarzi S et al. 2011. GM1 gangliosidosis and Morquio B disease: An update on genetic alterations and clinical findings. Biochim. Biophys. Acta 1812:782–90
    [Google Scholar]
  64. 64. 
    Okumiya T, Sakuraba H, Kase R, Sugiura T 2003. Imbalanced substrate specificity of mutant β-galactosidase in patients with Morquio B disease. Mol. Genet. Metab. 78:51–58
    [Google Scholar]
  65. 65. 
    Ogawa Y, Irisa M, Sano T, Yanagi Y, Furusawa E et al. 2018. Improvement in dysmyelination by the inhibition of microglial activation in a mouse model of Sandhoff disease. NeuroReport 29:962–67
    [Google Scholar]
  66. 66. 
    Sandhoff K. 1970. The hydrolysis of Tay-Sachs ganglioside (TSG) by human N-acetyl-β-D-hexosaminidase A. FEBS Lett 11:342–44
    [Google Scholar]
  67. 67. 
    Sandhoff K, Conzelmann E, Nehrkorn H 1977. Specificity of human liver hexosaminidases A and B against glycosphingolipids GM2 and GA2. Purification of the enzymes by affinity chromatography employing specific elution. Hoppe-Seyler's Z. Physiol. Chem. 358:779–87
    [Google Scholar]
  68. 68. 
    Hepbildikler ST, Sandhoff R, Kölzer M, Proia RL, Sandhoff K 2002. Physiological substrates for human lysosomal β-hexosaminidase S. J. Biol. Chem. 277:2562–72
    [Google Scholar]
  69. 69. 
    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. PNAS 75:3979–83
    [Google Scholar]
  70. 70. 
    Wendeler M, Werth N, Maier T, Schwarzmann G, Kolter T et al. 2006. The enzyme-binding region of human GM2-activator protein. FEBS J 273:982–91
    [Google Scholar]
  71. 71. 
    Leinekugel P, Michel S, Conzelmann E, Sandhoff K 1992. Quantitative correlation between the residual activity of β-hexosaminidase A and arylsulfatase A and the severity of the resulting lysosomal storage disease. Hum. Genet. 88:513–23
    [Google Scholar]
  72. 72. 
    Kytzia HJ, Sandhoff K 1985. Evidence for two different active sites on human β-hexosaminidase A. Interaction of GM2 activator protein with β-hexosaminidase A. J. Biol. Chem. 260:7568–72
    [Google Scholar]
  73. 73. 
    dos Santos MR, Tanaka A, sá Miranda MC, Ribeiro MG, Maia M, Suzuki K 1991. GM2-gangliosidosis B1 variant: analysis of β-hexosaminidase alpha gene mutations in 11 patients from a defined region in Portugal. Am. J. Hum. Genet. 49:886–90
    [Google Scholar]
  74. 74. 
    Meier EM, Schwarzmann G, Fürst W, Sandhoff K 1991. The human GM2 activator protein. A substrate specific cofactor of β-hexosaminidase A. J. Biol. Chem. 266:1879–87
    [Google Scholar]
  75. 75. 
    Sandhoff R, Hepbildikler ST, Jennemann R, Geyer R, Gieselmann V et al. 2002. Kidney sulfatides in mouse models of inherited glycosphingolipid disorders: determination by nano-electrospray ionization tandem mass spectrometry. J. Biol. Chem. 277:20386–98
    [Google Scholar]
  76. 76. 
    Allende ML, Cook EK, Larman BC, Nugent A, Brady JM et al. 2018. Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation. J. Lipid Res. 59:550–63
    [Google Scholar]
  77. 77. 
    Sango K, McDonald MP, Crawley JN, Mack ML, Tifft CJ et al. 1996. Mice lacking both subunits of lysosomal β-hexosaminidase display gangliosidosis and mucopolysaccharidosis. Nat. Genet. 14:348–52
    [Google Scholar]
  78. 78. 
    Fingerhut R, van der Horst GTJ, Verheijen FW, Conzelmann E 1992. Degradation of gangliosides by the lysosomal sialidase requires an activator protein. Eur. J. Biochem. 208:623–29
    [Google Scholar]
  79. 79. 
    Thomas GH. 2001. Disorders of glycoprotein degradation: α-mannosidosis, frucosidosis, and sialidosis. The Metabolic and Molecular Bases of Inherited Diseases C Scriver, A Beaudet, W Sly, D Valle 3507–33 New York: McGraw-Hill
    [Google Scholar]
  80. 80. 
    Zschoche A, Fürst W, Schwarzmann G, Sandhoff K 1994. Hydrolysis of lactosylceramide by human galactosylceramidase and GM1-β-galactosidase in a detergent-free system and its stimulation by sphingolipid activator proteins, sap-B and sap-C. Activator proteins stimulate lactosylceramide hydrolysis. Eur. J. Biochem. 222:83–90
    [Google Scholar]
  81. 81. 
    Hulkova H, Cervenkova M, Ledvinova J, Tochackova M, Hrebicek M et al. 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. 10:927–40
    [Google Scholar]
  82. 82. 
    Nilsson O, Svennerholm L 1982. Accumulation of glucosylceramide and glucosylsphingosine (psychosine) in cerebrum and cerebellum in infantile and juvenile Gaucher disease. J. Neurochem. 39:709–18
    [Google Scholar]
  83. 83. 
    Brady RO, Kanfer JN, Shapiro D 1965. Metabolism of glucocerebrosides. II. Evidence of an enzymatic deficiency in Gaucher's disease. Biochem. Biophys. Res. Commun. 18:221–25
    [Google Scholar]
  84. 84. 
    Patrick AD. 1965. A deficiency of glucocerevrosidase in Gaucher's disease. Biochem. J. 97:17C–24C
    [Google Scholar]
  85. 85. 
    Barton NW, Brady RO, Dambrosia JM, Di Bisceglie AM, Doppelt SH et al. 1991. Replacement therapy for inherited enzyme deficiency–macrophage-targeted glucocerebrosidase for Gaucher's disease. N. Engl. J. Med. 324:1464–70
    [Google Scholar]
  86. 86. 
    Krivit W, Peters C, Shapiro EG 1999. Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III. Curr. Opin. Neurol. 12:167–76
    [Google Scholar]
  87. 87. 
    Schueler UH, Kolter T, Kaneski CR, Blusztajn JK, Herkenham M et al. 2003. Toxicity of glucosyl-sphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3. Neurobiol. Dis. 14:595–601
    [Google Scholar]
  88. 88. 
    Taguchi YV, Liu J, Ruan J, Pacheco J, Zhang X et al. 2017. Glucosylsphingosine promotes α-synuclein pathology in mutant GBA-associated Parkinson's disease. J. Neurosci. 37:9617–31
    [Google Scholar]
  89. 89. 
    Balestrino R, Schapira AHV 2018. Glucocerebrosidase and Parkinson disease: molecular, clinical, and therapeutic implications. Neuroscientist 5:540–59
    [Google Scholar]
  90. 90. 
    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:Part 2377–82
    [Google Scholar]
  91. 91. 
    Doering T, Proia RL, Sandhoff K 1999. Accumulation of protein-bound epidermal glucosylceramides in β-glucocerebrosidase deficient type 2 Gaucher mice. FEBS Lett 447:167–70
    [Google Scholar]
  92. 92. 
    Breiden B, Sandhoff K 2014. The role of sphingolipid metabolism in cutaneous permeability barrier formation. Biochim. Biophys. Acta 1841:441–52
    [Google Scholar]
  93. 93. 
    Beck M, Moser HW, Sandhoff K 2015. Acid ceramidase deficiency: Farber lipogranulomatosis and spinal muscular atrophy associated with progressive myoclonic epilepsy. Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease RN Rosenberg, JM Pascual 395–402 Boston: Elsevier
    [Google Scholar]
  94. 94. 
    Gebai A, Gorelik A, Li Z, Illes K, Nagar B 2018. Structural basis for the activation of acid ceramidase. Nat. Commun. 9:1621
    [Google Scholar]
  95. 95. 
    Prensky AL, Ferreira G, Carr S, Moser HW 1967. Ceramide and ganglioside accumulation in Farbers lipogranulamatosis. Exp. Biol. Med. 126:725–28
    [Google Scholar]
  96. 96. 
    Farber S, Cohen J, Uzman LL 1957. Lipogranulomatosis; a new lipo-glycoprotein storage disease. J. Mt. Sinai Hosp. N.Y. 24:816–37
    [Google Scholar]
  97. 97. 
    Sugita M, Dulaney JT, Moser HW 1972. Ceramidase deficiency in Farber's disease (lipogranulomatosis). Science 178:1100–2
    [Google Scholar]
  98. 98. 
    Koch J, Gärtner S, Li CM, Quintern LE, Bernardo K et al. 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. 271:33110–15
    [Google Scholar]
  99. 99. 
    Matsuura F, Ohta M, Ioannou YA, Desnick RJ 1998. Human α-galactosidase A: characterization of the N-linked oligosaccharides on the intracellular and secreted glycoforms overexpressed by Chinese hamster ovary cells. Glycobiology 8:329–39
    [Google Scholar]
  100. 100. 
    Aerts JM, Groener JE, Kuiper S, Donker-Koopman WE, Strijland A et al. 2008. Elevated globotriaosylsphingosine is a hallmark of Fabry disease. PNAS 105:2812–17
    [Google Scholar]
  101. 101. 
    Togawa T, Takada M, Aizawa Y, Tsukimura T, Chiba Y, Sakuraba H 2014. Comparative study on mannose 6-phosphate residue contents of recombinant lysosomal enzymes. Mol. Genet. Metab. 111:369–73
    [Google Scholar]
  102. 102. 
    von Figura K, Gieselmann V, Jaeken J 2001. Metachromatic leukodystrophy. The Metabolic and Molecular Bases of Inherited Disease CR Scriver, AL Beaudet, WS Sly, D Valle 3695–724 New York: McGraw-Hill
    [Google Scholar]
  103. 103. 
    Alzheimer A. 1910. Beitraege zur Kenntnis der pathologischen Neuroglia und ihrer Beziehungen zu den Abbauvorgaengen im Nervengewebe. Nissl-Alzheimer's Histol. Histopathol. Arb 3:401
    [Google Scholar]
  104. 104. 
    Austin J. 1963. Recent studies in the metachromatic and globoid body forms of diffuse sclerosis. Brain Lipids and Lipoproteins and Leucodystrophies J Folch-Pi New York: Elsevier
    [Google Scholar]
  105. 105. 
    Austin J, Balasubramantan A, Pattabtraman T, Basu D, Bachhawat B 1963. A controlled study of enzymatic activities in three human disorders of glycolipid metabolism. J. Neurochem. 10:805–16
    [Google Scholar]
  106. 106. 
    Mehl E, Jatzkewitz H 1965. Evidence for the genetic block in metachromatic leucodystrophy (Ml). Biochem. Biophys. Res. Commun. 19:407–11
    [Google Scholar]
  107. 107. 
    Mehl E, Jatzkewitz H 1963. Über ein Cerebrosid-Schwefelsäureester spaltendes Enzym aus Schweineniere. Hoppe-Seyler's Z. Physiol. Chem. 331:292–94
    [Google Scholar]
  108. 108. 
    Krabbe K. 1916. A new familial, infantile form of a diffuse brain sclerosis. Brain 39:74–114
    [Google Scholar]
  109. 109. 
    Hagberg B, Kollberg H, Sourander P, Akesson HO 1970. Infantile globoid cell leukodystrophy (Krabbe's disease): a clinical and genetic study of 32 Swedish cases 1953–1967. Neuropediatrics 1:74–88
    [Google Scholar]
  110. 110. 
    Suzuki K, Suzuki Y 1970. Globoid cell leucodystrophy (Krabbe's disease): deficiency of galactocerebroside β-galactosidase. PNAS 66:302–9
    [Google Scholar]
  111. 111. 
    Chen YQ, Wenger DA 1993. Galactocerebrosidase from human urine: purification and partial characterization. Biochim. Biophys. Acta 1170:53–61
    [Google Scholar]
  112. 112. 
    Wenger DA, Suzuki K, Suzuki Y, Suzuki K 2001. Galactosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease). The Metabolic and Molecular Bases of Inherited Disease CR Scriver, AL Beaudet, WS Sly, D Valle 3669–94 New York: McGraw-Hill
    [Google Scholar]
  113. 113. 
    Svennerholm L, Vanier MT, Mansson JE 1980. Krabbe disease: a galactosylsphingosine (psychosine) lipidosis. J. Lipid Res. 21:53–64
    [Google Scholar]
  114. 114. 
    Suzuki K. 1998. Twenty five years of the “psychosine hypothesis”: a personal perspective of its history and present status. Neurochem. Res. 23:251–59
    [Google Scholar]
  115. 115. 
    Spiegel R, Bach G, Sury V, Mengistu G, Meidan B et al. 2005. A mutation in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: first report of saposin A deficiency in humans. Mol. Genet. Metab. 84:160–66
    [Google Scholar]
  116. 116. 
    Hill CH, Cook GM, Spratley SJ, Fawke S, Graham SC, Deane JE 2018. The mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex structure. Nat. Commun. 9:151
    [Google Scholar]
  117. 117. 
    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. 280:41125–28
    [Google Scholar]
  118. 118. 
    Sandhoff K, Kolter T, Harzer K 2001. Sphingolipid activator proteins. The Metabolic and Molecular Bases of Inherited Disease CR Scriver, AL Beaudet, WS Sly, D Valle 3371–89 New York: McGraw-Hill
    [Google Scholar]
  119. 119. 
    Fischer G, Jatzkewitz H 1975. The activator of cerebroside sulphatase. Purification from human liver and identification as a protein. Hoppe-Seyler's Z. Physiol. Chem. 356:605–13
    [Google Scholar]
  120. 120. 
    Ahn VE, Faull KF, Whitelegge JP, Fluharty AL, Privé GG 2003. Crystal structure of saposin B reveals a dimeric shell for lipid binding. PNAS 100:38–43
    [Google Scholar]
  121. 121. 
    Rossmann M, Schultz-Heienbrok R, Behlke J, Remmel N, Alings C et al. 2008. Crystal structures of human saposins C and D: implications for lipid recognition and membrane interactions. Structure 16:809–17
    [Google Scholar]
  122. 122. 
    Schwarzmann G, Breiden B, Sandhoff K 2015. Membrane-spanning lipids for an uncompromised monitoring of membrane fusion and intermembrane lipid transfer. J. Lipid Res. 56:1861–79
    [Google Scholar]
  123. 123. 
    Graf CG, Schulz C, Schmälzlein M, Heinlein C, Mönnich M et al. 2017. Synthetic glycoforms reveal carbohydrate-dependent bioactivity of human saposin D. Angew. Chem. Int. Ed. Engl. 56:5252–57
    [Google Scholar]
  124. 124. 
    Annunziata I, d'Azzo A 2017. Galactosialidosis: historic aspects and overview of investigated and emerging treatment options. Expert Opin. Orphan Drugs 5:131–41
    [Google Scholar]
  125. 125. 
    Futerman AH, van Meer G 2004. The cell biology of lysosomal storage disorders. Nat. Rev. Mol. Cell Biol. 5:554–65
    [Google Scholar]
  126. 126. 
    Pandey MK, Burrow TA, Rani R, Martin LJ, Witte D et al. 2017. Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease. Nature 543:108–12
    [Google Scholar]
  127. 127. 
    Jeyakumar M, Thomas R, Elliot-Smith E, Smith DA, van der Spoel AC et al. 2003. Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain 126:974–87
    [Google Scholar]
  128. 128. 
    Conzelmann E, Sandhoff K 1983. Partial enzyme deficiencies: residual activities and the development of neurological disorders. Dev. Neurosci. 6:58–71
    [Google Scholar]
  129. 129. 
    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. 63:1060–68
    [Google Scholar]
  130. 130. 
    Bierfreund U, Lemm T, Hoffmann A, Uhlhorn-Dierks G, Childs RA et al. 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. 24:295–300
    [Google Scholar]
  131. 131. 
    Werth N, Schuette CG, Wilkening G, Lemm T, Sandhoff K 2001. Degradation of membrane-bound ganglioside GM2 by β-hexosaminidase A. Stimulation by GM2 activator protein and lysosomal lipids. J. Biol. Chem. 276:12685–90
    [Google Scholar]
  132. 132. 
    Murugesan V, Chuang WL, Liu J, Lischuk A, Kacena K et al. 2016. Glucosylsphingosine is a key biomarker of Gaucher disease. Am. J. Hematol. 91:1082–89
    [Google Scholar]
  133. 133. 
    Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F et al. 2013. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341:1233158
    [Google Scholar]
  134. 134. 
    Sessa M, Lorioli L, Fumagalli F, Acquati S, Redaelli D et al. 2016. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet 388:476–87
    [Google Scholar]
  135. 135. 
    Fan JQ. 2008. A counterintuitive approach to treat enzyme deficiencies: use of enzyme inhibitors for restoring mutant enzyme activity. Biol. Chem. 389:1–11
    [Google Scholar]
  136. 136. 
    Platt FM. 2018. Emptying the stores: lysosomal diseases and therapeutic strategies. Nat. Rev. Drug Discov. 17:133–50
    [Google Scholar]
  137. 137. 
    Elstein D, Hollak C, Aerts JM, van Weely S, Maas M et al. 2004. Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease. J. Inherit. Metab. Dis. 27:757–66
    [Google Scholar]
  138. 138. 
    Platt FM, Neises GR, Reinkensmeier G, Townsend MJ, Perry VH et al. 1997. Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin. Science 276:428–31
    [Google Scholar]
  139. 139. 
    Gray-Edwards HL, Randle AN, Maitland SA, Benatti HR, Hubbard SM et al. 2018. Adeno-associated virus gene therapy in a sheep model of Tay-Sachs disease. Hum. Gene Ther. 29:312–26
    [Google Scholar]
  140. 140. 
    Bradbury AM, Peterson TA, Gross AL, Wells SZ, McCurdy VJ et al. 2017. AAV-mediated gene delivery attenuates neuroinflammation in feline Sandhoff disease. Neuroscience 340:117–25
    [Google Scholar]
  141. 141. 
    Cachon-Gonzalez MB, Zaccariotto E, Cox TM 2018. Genetics and therapies for GM2 gangliosidosis. Curr. Gene Ther. 18:68–89
    [Google Scholar]
  142. 142. 
    Niemir N, Rouviere L, Besse A, Vanier MT, Dmytrus J et al. 2018. Intravenous administration of scAAV9-Hexb normalizes lifespan and prevents pathology in Sandhoff disease mice. Hum. Mol. Genet. 27:954–68
    [Google Scholar]
  143. 143. 
    Hongo K, Ito K, Date T, Anan I, Inoue Y et al. 2018. The beneficial effects of long-term enzyme replacement therapy on cardiac involvement in Japanese Fabry patients. Mol. Genet. Metab. 124:143–51
    [Google Scholar]
  144. 144. 
    Arends M, Biegstraaten M, Wanner C, Sirrs S, Mehta A et al. 2018. Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study. J. Med. Genet. 55:351–58
    [Google Scholar]
  145. 145. 
    Weismann CM, Ferreira J, Keeler AM, Su Q, Qui L et al. 2015. Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan. Hum. Mol. Genet. 24:4353–64
    [Google Scholar]
  146. 146. 
    Deodato F, Procopio E, Rampazzo A, Taurisano R, Donati MA et al. 2017. The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression. Metab. Brain Dis. 32:1529–36
    [Google Scholar]
  147. 147. 
    van Echten G, Sandhoff K 1989. Modulation of ganglioside biosynthesis in primary cultured neurons. J. Neurochem. 52:207–14
    [Google Scholar]
  148. 148. 
    Breiden B, Sandhoff K 2018. Ganglioside metabolism and its inherited diseases. Gangliosides: Methods and Protocols S Sonnino, A Prinetti 97–141 New York: Springer
    [Google Scholar]
  149. 149. 
    Linke T, Wilkening G, Sadeghlar F, Mozcall H, Bernardo K et al. 2001. Interfacial regulation of acid ceramidase activity. Stimulation of ceramide degradation by lysosomal lipids and sphingolipid activator proteins. J. Biol. Chem. 276:5760–68
    [Google Scholar]
  150. 150. 
    Vogel A, Schwarzmann G, Sandhoff K 1991. Glycosphingolipid specificity of the human sulfatide activator protein. Eur. J. Biochem. 200:591–97
    [Google Scholar]
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