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Sphingolipids in Neurodegeneration

NeuroMolecular Medicine volume 12, pages 301–305 (2010)Cite this article

Abstract

Although the brain contains a high content of sphingolipids, we know relatively little about the roles that sphingolipids play in regulating neural functions. Once regarded only for their structural roles in maintaining the integrity of cellular and sub-cellular compartments, it is now apparent that many sphingolipid species are biologically active and play important roles in regulating signaling events. Recent technological and scientific advances are rapidly increasing our knowledge of the roles that sphingolipids play in regulating normal neural activity. Likewise, we are beginning to understand how perturbations in sphingolipid metabolism contribute to the pathogenesis of a variety of neurodegenerative conditions. In this special issue of NeuroMolecular Medicine, we present a series of review articles that summarize new and emerging technologies for the analysis of sphingolipids, sphingolipid metabolic pathways, and how dysfunctions in sphingolipid metabolism contribute to neurodegeneration in lysosomal storage disorders, Alzheimer’s disease and Multiple Sclerosis.

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References

  • Abulrob, A., Tauskela, J. S., Mealing, G., Brunette, E., Faid, K., & Stanimirovic, D. (2005). Protection by cholesterol-extracting cyclodextrins: A role for N-methyl-D-aspartate receptor redistribution. Journal of Neurochemistry, 92, 1477–1486.

    CAS  Article  PubMed  Google Scholar 

  • Assaife-Lopes, N., Sousa, V. C., Pereira, D. B., Ribeiro, J. A., Chao, M. V., & Sebastiao, A. M. (2010). Activation of adenosine A2A receptors induces TrkB translocation and increases BDNF-mediated phospho-TrkB localization in lipid rafts: Implications for neuromodulation. Journal of Neuroscience, 30, 8468–8480.

    CAS  Article  PubMed  Google Scholar 

  • Bajjalieh, S. M., Martin, T. F., & Floor, E. (1989). Synaptic vesicle ceramide kinase. A calcium-stimulated lipid kinase that co-purifies with brain synaptic vesicles. Journal of Biological Chemistry, 264, 14354–14360.

    CAS  PubMed  Google Scholar 

  • Bandaru, V. V., McArthur, J. C., Sacktor, N., Cutler, R. G., Knapp, E. L., Mattson, M. P., et al. (2007). Associative and predictive biomarkers of dementia in HIV-1-infected patients. Neurology, 68, 1481–1487.

    CAS  Article  PubMed  Google Scholar 

  • Bandaru, V. V., Troncoso, J., Wheeler, D., Pletnikova, O., Wang, J., Conant, K., et al. (2009). ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer’s but not normal brain. Neurobiology of Aging, 30, 591–599.

    CAS  Article  PubMed  Google Scholar 

  • Besshoh, S., Bawa, D., Teves, L., Wallace, M. C., & Gurd, J. W. (2005). Increased phosphorylation and redistribution of NMDA receptors between synaptic lipid rafts and post-synaptic densities following transient global ischemia in the rat brain. Journal of Neurochemistry, 93, 186–194.

    CAS  Article  PubMed  Google Scholar 

  • Blochl, A., & Thoenen, H. (1996). Localization of cellular storage compartments and sites of constitutive and activity-dependent release of nerve growth factor (NGF) in primary cultures of hippocampal neurons. Molecular and Cellular Neurosciences, 7, 173–190.

    CAS  Article  PubMed  Google Scholar 

  • Blood, P. D., & Voth, G. A. (2006). Direct observation of Bin/amphiphysin/Rvs (BAR) domain-induced membrane curvature by means of molecular dynamics simulations. Proceedings of the National Academy of Sciences of the United States of America, 103, 15068–15072.

    CAS  Article  PubMed  Google Scholar 

  • Brann, A. B., Scott, R., Neuberger, Y., Abulafia, D., Boldin, S., Fainzilber, M., et al. (1999). Ceramide signaling downstream of the p75 neurotrophin receptor mediates the effects of nerve growth factor on outgrowth of cultured hippocampal neurons. Journal of Neuroscience, 19, 8199–8206.

    CAS  PubMed  Google Scholar 

  • Bryant, M. R., Marta, C. B., Kim, F. S., & Bansal, R. (2009). Phosphorylation and lipid raft association of fibroblast growth factor receptor-2 in oligodendrocytes. Glia, 57, 935–946.

    CAS  Article  PubMed  Google Scholar 

  • Coogan, A. N., O’Neill, L. A., & O’Connor, J. J. (1999). The P38 mitogen-activated protein kinase inhibitor SB203580 antagonizes the inhibitory effects of interleukin-1beta on long-term potentiation in the rat dentate gyrus in vitro. Neuroscience, 93, 57–69.

    CAS  Article  PubMed  Google Scholar 

  • Darios, F., Wasser, C., Shakirzyanova, A., et al. (2009). Sphingosine facilitates SNARE complex assembly and activates synaptic vesicle exocytosis. Neuron, 62, 683–694.

    CAS  Article  PubMed  Google Scholar 

  • Davis, C. N., Tabarean, I., Gaidarova, S., Behrens, M. M., & Bartfai, T. (2006). IL-1beta induces a MyD88-dependent and ceramide-mediated activation of Src in anterior hypothalamic neurons. Journal of Neurochemistry, 98, 1379–1389.

    CAS  Article  PubMed  Google Scholar 

  • Day, C. A., & Kenworthy, A. K. (2009). Tracking microdomain dynamics in cell membranes. Biochimica et Biophysica Acta, 1788, 245–253.

    CAS  Article  PubMed  Google Scholar 

  • Delint-Ramirez, I., Fernandez, E., Bayes, A., Kicsi, E., Komiyama, N. H., & Grant, S. G. (2010). In vivo composition of NMDA receptor signaling complexes differs between membrane subdomains and is modulated by PSD-95 and PSD-93. Journal of Neuroscience, 30, 8162–8170.

    CAS  Article  PubMed  Google Scholar 

  • Fasano, C., Miolan, J. P., & Niel, J. P. (2003). Modulation by C2 ceramide of the nicotinic transmission within the coeliac ganglion in the rabbit. Neuroscience, 116, 753–759.

    CAS  Article  PubMed  Google Scholar 

  • Frank, C., Giammarioli, A. M., Pepponi, R., Fiorentini, C., & Rufini, S. (2004). Cholesterol perturbing agents inhibit NMDA-dependent calcium influx in rat hippocampal primary culture. FEBS Letters, 566, 25–29.

    CAS  Article  PubMed  Google Scholar 

  • Fullekrug, J., & Simons, K. (2004). Lipid rafts and apical membrane traffic. Annals of the New York Academy of Sciences, 1014, 164–169.

    Article  PubMed  Google Scholar 

  • Furukawa, K., & Mattson, M. P. (1998). The transcription factor NF-kappaB mediates increases in calcium currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-alpha in hippocampal neurons. Journal of Neurochemistry, 70, 1876–1886.

    CAS  Article  PubMed  Google Scholar 

  • Furuya, S., Mitoma, J., Makino, A., & Hirabayashi, Y. (1998). Ceramide and its interconvertible metabolite sphingosine function as indispensable lipid factors involved in survival and dendritic differentiation of cerebellar Purkinje cells. Journal of Neurochemistry, 71, 366–377.

    CAS  Article  PubMed  Google Scholar 

  • Harlan, J. E., Hajduk, P. J., Yoon, H. S., & Fesik, S. W. (1994). Pleckstrin homology domains bind to phosphatidylinositol-4, 5-bisphosphate. Nature, 371, 168–170.

    CAS  Article  PubMed  Google Scholar 

  • Haughey, N. J., Cutler, R. G., Tamara, A., McArthur, J. C., Vargas, D. L., Pardo, C. A., et al. (2004). Perturbation of sphingolipid metabolism and ceramide production in HIV-dementia. Annals of Neurology, 55, 257–267.

    CAS  Article  PubMed  Google Scholar 

  • Hering, H., Lin, C. C., & Sheng, M. (2003). Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability. Journal of Neuroscience, 23, 3262–3271.

    CAS  PubMed  Google Scholar 

  • Hirao, M., Sato, N., Kondo, T., Yonemura, S., Monden, M., Sasaki, T., et al. (1996). Regulation mechanism of ERM (ezrin/radixin/moesin) protein/plasma membrane association: Possible involvement of phosphatidylinositol turnover and Rho-dependent signaling pathway. Journal of Cell Biology, 135, 37–51.

    CAS  Article  PubMed  Google Scholar 

  • Inokuchi, J., Mizutani, A., Jimbo, M., et al. (1998). A synthetic ceramide analog (L-PDMP) up-regulates neuronal function. Annals of the New York Academy of Sciences, 845, 219–224.

    CAS  Article  PubMed  Google Scholar 

  • Ito, A., & Horigome, K. (1995). Ceramide prevents neuronal programmed cell death induced by nerve growth factor deprivation. Journal of Neurochemistry, 65, 463–466.

    CAS  Article  PubMed  Google Scholar 

  • Jeon, H. J., Lee, D. H., Kang, M. S., Lee, M. O., Jung, K. M., Jung, S. Y., et al. (2005). Dopamine release in PC12 cells is mediated by Ca(2+)-dependent production of ceramide via sphingomyelin pathway. Journal of Neurochemistry, 95, 811–820.

    CAS  Article  PubMed  Google Scholar 

  • Kajimoto, T., Okada, T., Yu, H., Goparaju, S. K., Jahangeer, S., & Nakamura, S. (2007). Involvement of sphingosine-1-phosphate in glutamate secretion in hippocampal neurons. Molecular and Cellular Biology, 27, 3429–3440.

    CAS  Article  PubMed  Google Scholar 

  • Kutateladze, T. G., Ogburn, K. D., Watson, W. T., de Beer, T., Emr, S. D., Burd, C. G., et al. (1999). Phosphatidylinositol 3-phosphate recognition by the FYVE domain. Molecular Cell, 3, 805–811.

    CAS  Article  PubMed  Google Scholar 

  • Levental, I., Grzybek, M., & Simons, K. (2010). Greasing their way: Lipid modifications determine protein association with membrane rafts. Biochemistry, 49, 6305–6316.

    CAS  Article  PubMed  Google Scholar 

  • Liu, Y., Fisher, D. A., & Storm, D. R. (1993). Analysis of the palmitoylation and membrane targeting domain of neuromodulin (GAP-43) by site-specific mutagenesis. Biochemistry, 32, 10714–10719.

    CAS  Article  PubMed  Google Scholar 

  • Low, M. G. (1989). Glycosyl-phosphatidylinositol: A versatile anchor for cell surface proteins. The FASEB Journal, 3, 1600–1608.

    CAS  PubMed  Google Scholar 

  • Magee, A. I., Gutierrez, L., Marshall, C. J., & Hancock, J. F. (1989). Targeting of oncoproteins to membranes by fatty acylation. Journal of Cell Science. Supplement, 11, 149–160.

    CAS  PubMed  Google Scholar 

  • Medkova, M., & Cho, W. (1999). Interplay of C1 and C2 domains of protein kinase C-alpha in its membrane binding and activation. Journal of Biological Chemistry, 274, 19852–19861.

    CAS  Article  PubMed  Google Scholar 

  • Numakawa, T., Nakayama, H., Suzuki, S., et al. (2003). Nerve growth factor-induced glutamate release is via p75 receptor, ceramide, and Ca(2+) from ryanodine receptor in developing cerebellar neurons. Journal of Biological Chemistry, 278, 41259–41269.

    CAS  Article  PubMed  Google Scholar 

  • Owen, D. M., Williamson, D., Rentero, C., & Gaus, K. (2009). Quantitative microscopy: Protein dynamics and membrane organisation. Traffic, 10, 962–971.

    CAS  Article  PubMed  Google Scholar 

  • Ping, S. E., & Barrett, G. L. (1998). Ceramide can induce cell death in sensory neurons, whereas ceramide analogues and sphingosine promote survival. Journal of Neuroscience Research, 54, 206–213.

    CAS  Article  PubMed  Google Scholar 

  • Rohrbough, J., Rushton, E., Palanker, L., Woodruff, E., Matthies, H. J., Acharya, U., et al. (2004). Ceramidase regulates synaptic vesicle exocytosis and trafficking. Journal of Neuroscience, 24, 7789–7803.

    CAS  Article  PubMed  Google Scholar 

  • Santagata, S., Boggon, T. J., Baird, C. L., Gomez, C. A., Zhao, J., Shan, W. S., et al. (2001). G-protein signaling through tubby proteins. Science, 292, 2041–2050.

    CAS  Article  PubMed  Google Scholar 

  • Stahelin, R. V. (2009). Lipid binding domains: More than simple lipid effectors. Journal of Lipid Research, 50 Suppl, S299–S304.

    PubMed  Google Scholar 

  • Stahelin, R. V., Long, F., Peter, B. J., Murray, D., De Camilli, P., McMahon, H. T., et al. (2003). Contrasting membrane interaction mechanisms of AP180 N-terminal homology (ANTH) and epsin N-terminal homology (ENTH) domains. Journal of Biological Chemistry, 278, 28993–28999.

    CAS  Article  PubMed  Google Scholar 

  • Stokoe, D., Macdonald, S. G., Cadwallader, K., Symons, M., & Hancock, J. F. (1994). Activation of Raf as a result of recruitment to the plasma membrane. Science, 264, 1463–1467.

    CAS  Article  PubMed  Google Scholar 

  • Swartz, K. J. (2008). Sensing voltage across lipid membranes. Nature, 456, 891–897.

    CAS  Article  PubMed  Google Scholar 

  • Tabarean, I. V., Korn, H., & Bartfai, T. (2006). Interleukin-1beta induces hyperpolarization and modulates synaptic inhibition in preoptic and anterior hypothalamic neurons. Neuroscience, 141, 1685–1695.

    CAS  Article  PubMed  Google Scholar 

  • Thelen, M., Rosen, A., Nairn, A. C., & Aderem, A. (1991). Regulation by phosphorylation of reversible association of a myristoylated protein kinase C substrate with the plasma membrane. Nature, 351, 320–322.

    CAS  Article  PubMed  Google Scholar 

  • Wheeler, D., Knapp, E., Bandaru, V. V., Wang, Y., Knorr, D., Poirier, C., et al. (2009). Tumor necrosis factor-alpha-induced neutral sphingomyelinase-2 modulates synaptic plasticity by controlling the membrane insertion of NMDA receptors. Journal of Neurochemistry, 109, 1237–1249.

    CAS  Article  PubMed  Google Scholar 

  • Yang, S. N. (2000). Ceramide-induced sustained depression of synaptic currents mediated by ionotropic glutamate receptors in the hippocampus: An essential role of postsynaptic protein phosphatases. Neuroscience, 96, 253–258.

    CAS  Article  PubMed  Google Scholar 

  • Yin, X., Zafrullah, M., Lee, H., Haimovitz-Friedman, A., Fuks, Z., & Kolesnick, R. (2009). A ceramide-binding C1 domain mediates kinase suppressor of ras membrane translocation. Cellular Physiology and Biochemistry, 24, 219–230.

    CAS  Article  PubMed  Google Scholar 

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  1. Department of Neurology, Richard T. Johnson Division of Neuroimmunology and Neurological Infections, The Johns Hopkins University School of Medicine, Meyer 6-109, 600 North Wolfe Street, Baltimore, MD, 21287, USA

    Norman J. Haughey

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  1. Norman J. Haughey
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Correspondence to Norman J. Haughey.

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Haughey, N.J. Sphingolipids in Neurodegeneration. Neuromol Med 12, 301–305 (2010). https://doi.org/10.1007/s12017-010-8135-5

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  • DOI: https://doi.org/10.1007/s12017-010-8135-5

Keywords

  • Sphingolipid
  • Sphingomyelin
  • Ceramide
  • Neurodegeneration
  • Alzheimer’s
  • HIV
  • Multiple sclerosis
  • Neurodegeneration
  • Synapse