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In Search of a Solution to the Sphinx-Like Riddle of GM1

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Abstract

Among the many glycoconjugates contributing to the sugar code, gangliosides have drawn special attention owing to their predominance as the major sialoglycoconjugate category within the nervous system. However, their occurrence, albeit at lower levels, appears ubiquitous in vertebrate cells and even some invertebrate tissues. Now that over 100 gangliosides have been structurally characterized, their diverse physiological functions constitute a remaining enigma. This has been especially true of GM1, for which a surprising array of functions has already been revealed. Our current research has focused on two areas of GM1 function: (a) signaling induced in neural and immune cells by cross-linking of GM1 in the plasma membrane that leads to activation of TRPC5 (transient receptor potiential, canonical form 5) channels, a process important in neuritogenesis and autoimmune suppression; (b) activation by GM1 of a sodium-calcium exchanger (NCX) in the inner membrane of the nuclear envelope (NE) with resulting modulation of nuclear and cellular calcium. The latter has a role in maintaining neuronal viability, loss of which renders neurons vulnerable to Ca2+ overload. Pathological manifestations in mutant mice and their cultured neurons lacking GM1 have shown dramatic rescue with a membrane permeable derivative of GM1 that enters the nucleus and restores NCX activity. Nuclear function of GM1 is related to the presence of neuraminidase in the NE, an enzyme that generates GM1 through hydrolysis of GD1a. A different isoform of this enzyme was found in each of the two membranes of the NE.

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Abbreviations

CtxB:

B subunit of cholera toxin

ER:

Endoplasmic reticulum

Gal-1:

Galectin-1

IP:

Intraperitoneal

N’ase:

Neuraminidase

NCX:

Sodium-calcium exchanger

NE:

Nuclear envelope

Teff:

Effector T cell

Treg:

Regulatory T cell

TRPC5:

Transient receptor potential, isoform 5 of canonical subgroup

References

  1. Svennerholm L (1963) Chromatographic separation of human brain gangliosides. J Neurochem 10:613–623

    Article  CAS  PubMed  Google Scholar 

  2. Kuhn R, Wiegandt H (1963) Die Konstitution der Ganglio-N-tetraose und des Gangliosids G1. Chemische Berichte 96:866–880

    Article  CAS  Google Scholar 

  3. Ledeen R, Salsman K, Gonatas J, Taghavy A (1965) Structure comparison of the major monosialogangliosides from brains of normal human, gargoylism, and late infantile systemic lipidosis. J Neuropath Exp Neurol 24:341–351

    Article  CAS  PubMed  Google Scholar 

  4. Forman DS, Ledeen RW (1972) Axonal transport of gangliosides in the goldfish optic nerve. Science 177:630–633

    Article  CAS  PubMed  Google Scholar 

  5. Ledeen RW (1978) Ganglioside structures and distribution: are they localized at the nerve ending? J Supramolec Struct 8:1–17

    Article  CAS  Google Scholar 

  6. Yu RK, Yanagisawa M, Ariga T (2007) Glycosphingolipid structures. In: Kamerling JP (ed) Comprehensive glycoscience. Elsevier, Oxford, UK, pp 73–122

    Chapter  Google Scholar 

  7. Simons K, van Meer G (1988) Lipid sorting in epithelial cells. Biochemistry 27:6197–6202

    Article  CAS  PubMed  Google Scholar 

  8. Hakomori S-I, Handa K, Iwabuchi K, Yamamura S, Prinetti A (1998) New insights in glycosphingolipid function: “glycosignaling domain”, a cell surface assembly of glycosphingolipids with signal transducer molecules, involved in cell adhesion coupled with signaling. Glycobiology 8:xi–xix

    CAS  PubMed  Google Scholar 

  9. Wu G, Ledeen RW (1994) Gangliosides as modulators of neuronal calcium. Prog Brain Res 101:101–112

    Article  CAS  PubMed  Google Scholar 

  10. Ledeen RW, Wu G (2002) Ganglioside function in calcium homeostasis and signaling. Neurochem Res 27:637–647

    Article  CAS  PubMed  Google Scholar 

  11. Byrne MC, Ledeen RW, Roisen FJ, Yorke G, Sclafani J (1983) Ganglioside-induced neuritogenesis: verification that gangliosides are the active agents, and comparison of molecular species. J Neurochem 41:1214–1222

    Article  CAS  PubMed  Google Scholar 

  12. Wu G, Ledeen RW (1991) Stimulation of neurite outgrowth in neuroblastoma cells by neuraminidase: putative role of GM1 ganglioside in differentiation. J Neurochem 56:95–104

    Article  CAS  PubMed  Google Scholar 

  13. Hasegawa T, Yamaguchi K, Wada T, Takeda A, Itoyama Y, Miyagi T (2000) Molecular cloning of mouse ganglioside sialidase and its increased expression in Neuro2a cell differentiation. J Biol Chem 275:8007–8015

    Article  CAS  PubMed  Google Scholar 

  14. Dixon SJ, Stewart D, Grinstein S, Spiegel S (1987) Transmembrane signaling by the B subunit of cholera toxin: increased cytoplasmic free calcium in rat lymphocytes. J Cell Biol 105:1153–1161

    Article  CAS  PubMed  Google Scholar 

  15. Fang Y, Xie X, Ledeen RW, Wu G (2002) Characterization of cholera toxin B subunit induced Ca2+ influx in neuroblastoma cells: evidence for a voltage independent GM1 ganglioside-associated Ca2+ channel. J Neurosci Res 69:669–680

    Article  CAS  PubMed  Google Scholar 

  16. Wu G, Lu Z-H, Obukhov AG, Nowycky MC, Ledeen RW (2007) Induction of calcium influx through TRPC5 channels by cross-linking of GM1 ganglioside associated with alpha5beta1 integrin initiates neurite outgrowth. J Neurosci 27:7447–7458

    Article  CAS  PubMed  Google Scholar 

  17. Clapham DE, Runnels LW, Strubing C (2001) The TRP ion channel family. Nature Rev Neurosci 2:387–396

    Article  CAS  Google Scholar 

  18. Montell C (2004) Exciting trips for TRPs. Nat Cell Biol 6:690–692

    Article  CAS  PubMed  Google Scholar 

  19. Wu G, Ledeen RW (2010) In Preparation

  20. Kopitz J, von Reitzenstein C, Burchert M, Cantz M, Gabius H-J (1998) Galectin-1 is a major receptor for ganglioside GM1, a product of the growth-controlling activity of a cell surface ganglioside sialidase, on human neuroblastoma cells in culture. J Biol Chem 273:11205–11211

    Article  CAS  PubMed  Google Scholar 

  21. Wang J, Lu Z-H, Gabius H-J, Rohowsky-Kochan C, Ledeen RW, Wu G (2009) Cross-Linking of GM1 ganglioside by galectin-1 mediates regulatory T cell activity involving TRPC5 channel activation: possible role in suppressing experimental autoimmune encephalomyelitis. J Immunol 182:4036–4045

    Article  CAS  PubMed  Google Scholar 

  22. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164

    CAS  PubMed  Google Scholar 

  23. Jiang H, Chess L (2006) Regulation of immune responses by T cells. New Eng J Med 354:1166–1176

    Article  CAS  PubMed  Google Scholar 

  24. Garin MI et al (2007) Galectin-1: a key effector of regulation mediated by CD4+CD25+ T cells. Blood 109:2058–2065

    Article  CAS  PubMed  Google Scholar 

  25. Brumeanu TD, Preda-Pais A, Stoica C, Bona C, Casares S (2007) Differential partitioning and trafficking of GM gangliosides and cholesterol-rich lipid rafts in thymic and spenic CD4 T cells. Mol Immunol 44:530–540

    Article  CAS  PubMed  Google Scholar 

  26. Rabinovich GA, Toscano MA (2009) Turning ‘sweet’ on immunity: galectin-glycan interactions in immune tolerance and inflammation. Nature Rev Immunol 9:338–352

    Article  CAS  Google Scholar 

  27. André S, Sanchez-Ruderisch H, Nakagawa H, Bucholz M et al (2007) Tumor suppressor p16INK4a: modulator of glycomic profile and galectin-1 expression to increase susceptibility to carbohydrate-dependent induction of anoikis in pancreatic carcinoma cells. FEBS J 274:3233–3256

    Article  PubMed  Google Scholar 

  28. Toscano MA, Bianco GA, Ilarregui JM, Croci DO, Correale J, Hernandez JD, Zwirner NW, Poirer F, Riley EM, Baum LG, Rabinovich GA (2007) Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nat Immunol 8:825–834

    Article  CAS  PubMed  Google Scholar 

  29. Offner H, Celnik B, Bringman TS, Casentini-Borocz D, Nedwin GE, Vandenbark AA (1990) Recombinant human β-galactoside binding lectin suppresses clinical and histological signs of experimental autoimmune encephalomyelitis. J Neuroimmunol 28:177–184

    Article  CAS  PubMed  Google Scholar 

  30. Perone MJ, Bertera S, Shufesky WJ, Divito SJ, Montecalvo A, Mathers AR, Larregina AT, Pang M, Seth N, Wucherpfennig KW, Trucco M, Baum LG, Morelli AE (2009) Suppression of autoimmune diabetes by soluble galectin-1. J Immunol 182:2641–2653

    Article  CAS  PubMed  Google Scholar 

  31. Sobel DO, Yankelevich B, Goyal D, Nelson D, Mazumder A (1998) The B-subunit of cholera toxin induces immunoregulatory cells and prevents diabetes in the NOD mouse. Diabetes 47:186–191

    Article  CAS  PubMed  Google Scholar 

  32. Salmond RJ, Luross JA, Williams NA (2002) Immune modulation by the cholera-like enterotoxins. Exp Rev Mol Med 4:1–16

    Article  Google Scholar 

  33. Keenan TW, Morré DJ, Huang CM (1972) Distribution of gangliosides among subcellular fractions from rat liver and bovine mammary gland. FEBS Lett 24:204–208

    Article  CAS  PubMed  Google Scholar 

  34. Matyas GR, Morre DJ (1987) Subcellular distribution and biosynthesis of rat liver gangliosides. Biochim Biophys Acta 921:599–614

    CAS  PubMed  Google Scholar 

  35. Katoh N, Kira T, Yuasa A (1993) Protein kinase C substrates and ganglioside inhibitors in bovine mammary nuclei. J Dairy Sci 76:3400–3409

    Article  CAS  PubMed  Google Scholar 

  36. Wu G, Lu Z-H, Ledeen RW (1995) Induced and spontaneous neuritogenesis are associated with enhanced expression of ganglioside GM1 in the nuclear membrane. J Neurosci 15:3739–3746

    CAS  PubMed  Google Scholar 

  37. Saito M, Sugiyama K (2002) Characterization of nuclear gangliosides in rat brain: concentration, composition, and developmental changes. Arch Biochem Biophys 398:153–159

    Article  CAS  PubMed  Google Scholar 

  38. Gilchrist JSC, Pierce GN (1993) Identification and purification of a calcium-binding protein in hepatic nuclear membranes. J Biol Chem 268:4291–4299

    CAS  PubMed  Google Scholar 

  39. Xie X, Wu G, Lu Z-H, Ledeen RW (2002) Potentiation of a sodium-calcium exchanger in the nuclear envelope by nuclear GM1 ganglioside. J Neurochem 81:1185–1195

    Article  CAS  PubMed  Google Scholar 

  40. Garner MH (2002) Na, K-ATPase in the nuclear envelope regulates Na+:K+gradients in hepatocyte nuclei. J Membr Biol 187:97–115

    Article  CAS  PubMed  Google Scholar 

  41. Palmer AE, Jin C, Reed JC, Tsien RY (2004) Bcl-2-mediated alterations in endoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor. Proc Natl Acad Sci USA 101:17404–17409

    Article  CAS  PubMed  Google Scholar 

  42. Miyawaki A, Griesbeck O, Heim R, Tsien RY (1999) Dynamic and quantitative Ca2+ measurements using improved cameleons. Proc Natl Acad Sci USA 96:2135–2140

    Article  CAS  PubMed  Google Scholar 

  43. Wu G, Xie X, Lu Z-H, Ledeen RW (2009) Sodium-calcium exchanger complexed with GM1 ganglioside in nuclear membrane transfers calcium from nucleoplasm to endoplasmic reticulum. Proc Natl Acad Sci USA 106:10829–10834

    Article  CAS  PubMed  Google Scholar 

  44. Kofuji P, Lederer WJ, Schulze DH (1994) Mutually exclusive and cassette exons underlie alternatively spliced isoforms of the Na+/Ca2+ exchanger. J Biol Chem 269:5145–5149

    CAS  PubMed  Google Scholar 

  45. He S, Ruknudin A, Bambrick LL, Lederer WJ, Schulze DH (1998) Isoform-specific regulation of the Na+/Ca2+ exchanger in rat astrocytes and neurons by PKA. J Neurosci 18:4833–4841

    CAS  PubMed  Google Scholar 

  46. Ledeen RW, Wu G (2006) Gangliosides of the nuclear membrane: a crucial locus of cytoprotective modulation. J Cellular Biochem 97:893–903

    Article  CAS  Google Scholar 

  47. Saito M, Fronda LL, Yu RK (1996) Sialidase activity in nuclear membranes of rat brain. J Neurochem 66:2205–2208

    Article  CAS  PubMed  Google Scholar 

  48. Wang J, Wu G, Miyagi T, Lu Z-H, Ledeen RW (2009) Sialidase occurs in both membranes of the nuclear envelope and hydrolyzes endogenous GD1a. J Neurochem 111:547–554

    Article  CAS  PubMed  Google Scholar 

  49. Mattson MP, Chan SL (2003) Calcium orchestrates apoptosis. Nat Cell Biol 5:1041–1043

    Article  CAS  PubMed  Google Scholar 

  50. Liu Y, Wada R, Kawai H, Sango K, Deng C, Tai T, McDonald MP, Araujo K, Crawley JN, Bierfreund U et al (1999) A genetic model of substrate deprivation therapy for a glycosphingolipid storage disorder. J Clin Invest 103:497–505

    Article  CAS  PubMed  Google Scholar 

  51. Wu G, Lu Z-H, Wang J, Wang Y, Xie X, Meyenhofer MF, Ledeen RW (2005) Enhanced susceptibility to kainate-induced seizures, neuronal apoptosis, and death in mice lacking gangliotetraose gangliosides: protection with LIGA 20, a membrane-permeant analog of GM1. J Neurosci 23:11014–11022

    Article  Google Scholar 

  52. Manev H, Favaron M, Vicini S, Guidotti A, Costa E (1990) Glutamate-induced neuronal death in primary cultures of cerebellar granule cells: protection by synthetic derivatives of endogenous sphingolipids. J Pharmacol Exp Ther 252:419–427

    CAS  PubMed  Google Scholar 

  53. Wu G, Lu Z-H, Xie X, Ledeen RW (2004) Susceptibility of cerebellar granule neurons from GM2/GD2 synthase-null mice to apoptosis induced by glutamate excitotoxicity and elevated KCl: rescue by GM1 and LIGA20. Glycoconj J 21:305–313

    Article  CAS  PubMed  Google Scholar 

  54. Gabius H-J (ed) (2009) The sugar code, fundamentals of glycosciences. Wiley-VCH, Weinheim, Germany

    Google Scholar 

  55. Mutoh T, Tokuda A, Miyadai T, Hamaguchi M, Fujiki N (1995) Ganglioside GM1 binds to the Trk protein and regulates receptor function. Proc Natl Acad Sci USA 92:5087–5091

    Article  CAS  PubMed  Google Scholar 

  56. Wu G, Lu Z-H, Ledeen RW (1997) Interaction of the δ-opioid receptor with GM1 ganglioside: conversion from inhibitory to excitatory mode. Mol Brain Res 44:341–346

    Article  CAS  PubMed  Google Scholar 

  57. Martinez Z, Zhu M, Hans S, Fink AL (2007) GM1 specifically interacts with alpha-synuclein and inhibits fibrillation. Biochemistry 46:1868–1877

    Article  CAS  PubMed  Google Scholar 

  58. Sano R, Ida Annunziata, Patterson A, Moshiach S, Gomero E, Opferman J, Forte M, d’Azzo A (2009) GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca2+-dependent mitochondrial apoptosis. Molecular Cell 36:500–511

    Article  CAS  PubMed  Google Scholar 

  59. Wang Y, Tsui Z, Yang F (1999) Antagonistic effects of ganglioside GM1 and GM3 on the activity and conformation of sarcoplasmic reticulum Ca2+-ATPase. FEBS Lett 457:144–148

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

Supported by grants from the NIH and NMSS.

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Authors and Affiliations

  1. Department of Neurology and Neurosciences, New Jersey Medical School, UMDNJ, 185 So. Orange Ave., MSB-H506, Newark, NJ, 07103, USA

    Robert W. Ledeen & Gusheng Wu

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  1. Robert W. Ledeen
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  2. Gusheng Wu
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Correspondence to Robert W. Ledeen.

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A note of special appreciation is due Dr. Lajtha, affectionately known as Abel by most everyone in the field. He has given most generously of his time and talent over many years toward building the pillars of what has come to be recognized as the mature discipline of neurochemistry. The journal he created 35 years ago and edited to the present time has been one such pillar, an essential vehicle for publication of findings considered controversial as well as mainstream. Handbook of Neurochemistry and Molecular Neurobiology, another editorial creation of his, has become an essential encyclopedia for working neuroscientists. Abel is one who will have to stoop a bit when passing through portals made for giants. On a personal note, it has been my good fortune to benefit on several occasions from Abel’s generosity of spirit and sound judgement, whether preparing a manuscript, serving together on committees, evaluating new discoveries, or negotiating a ski slope. Abel’s contributions to science and warm personal friendship will be long remembered and appreciated.

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Ledeen, R.W., Wu, G. In Search of a Solution to the Sphinx-Like Riddle of GM1. Neurochem Res 35, 1867–1874 (2010). https://doi.org/10.1007/s11064-010-0286-0

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