Skip to main content

Advertisement

SpringerLink
Log in

Sphingolipids as Regulators of Neuro-Inflammation and NADPH Oxidase 2

  • Review Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

Neuro-inflammation accompanies numerous neurological disorders and conditions where it can be associated with a progressive neurodegenerative pathology. In a similar manner, alterations in sphingolipid metabolism often accompany or are causative features in degenerative neurological conditions. These include dementias, motor disorders, autoimmune conditions, inherited metabolic disorders, viral infection, traumatic brain and spinal cord injury, psychiatric conditions, and more. Sphingolipids are major regulators of cellular fate and function in addition to being important structural components of membranes. Their metabolism and signaling pathways can also be regulated by inflammatory mediators. Therefore, as certain sphingolipids exert distinct and opposing cellular roles, alterations in their metabolism can have major consequences. Recently, regulation of bioactive sphingolipids by neuro-inflammatory mediators has been shown to activate a neuronal NADPH oxidase 2 (NOX2) that can provoke damaging oxidation. Therefore, the sphingolipid-regulated neuronal NOX2 serves as a mechanistic link between neuro-inflammation and neurodegeneration. Moreover, therapeutics directed at sphingolipid metabolism or the sphingolipid-regulated NOX2 have the potential to alleviate neurodegeneration arising out of neuro-inflammation.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Abou Daher, A., Francis, M., Azzam, P., Ahmad, A., Eid, A. A., Fornoni, A., et al. (2020). Modulation of radiation-induced damage of human glomerular endothelial cells by SMPDL3B. FASEB Journal, 34(6), 7915–7926.

    Article  CAS  PubMed  Google Scholar 

  • Alayoubi, A. M., Wang, J. C., Au, B. C., Carpentier, S., Garcia, V., Dworski, S., et al. (2013). Systemic ceramide accumulation leads to severe and varied pathological consequences. EMBO Molecular Medicine, 5(6), 827–842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alpaugh, M., Galleguillos, D., Forero, J., Morales, L. C., Lackey, S. W., Kar, P., et al. (2017). Disease-modifying effects of ganglioside GM1 in Huntington’s disease models. EMBO Molecular Medicine, 9(11), 1537–1557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Annunziata, I., Bouchè, V., Lombardi, A., Settembre, C., & Ballabio, A. (2007). Multiple sulfatase deficiency is due to hypomorphic mutations of the SUMF1 gene. Human Mutation, 28(9), 928–928.

    Article  PubMed  Google Scholar 

  • Ashe, K. M., Budman, E., Bangari, D. S., Siegel, C. S., Nietupski, J. B., Wang, B., et al. (2015). Efficacy of enzyme and substrate reduction therapy with a novel antagonist of glucosylceramide synthase for Fabry disease. Molecular Medicine, 21(1), 389–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bandaru, V. V., McArthur, J. C., Sacktor, N., Cutler, R. G., Knapp, E. L., Mattson, M. P., & Haughey, N. J. (2007). Associative and predictive biomarkers of dementia in HIV-1–infected patients. Neurology, 68(18), 1481–1487.

    Article  CAS  PubMed  Google Scholar 

  • Bandaru, V. V. R., Mielke, M. M., Sacktor, N., McArthur, J. C., Grant, I., Letendre, S., et al. (2013). A lipid storage–like disorder contributes to cognitive decline in HIV-infected subjects. Neurology, 81(17), 1492–1499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bang, J., Spina, S., & Miller, B. L. (2015). Frontotemporal dementia. The Lancet, 386(10004), 1672–1682.

    Article  Google Scholar 

  • Bansal, R., Winkler, S., & Bheddah, S. (1999). Negative regulation of oligodendrocyte differentiation by galactosphingolipids. Journal of Neuroscience, 19(18), 7913–7924.

    Article  CAS  PubMed  Google Scholar 

  • Bär, J., Linke, T., Ferlinz, K., Neumann, U., Schuchman, E. H., & Sandhoff, K. (2001). Molecular analysis of acid ceramidase deficiency in patients with Farber disease. Human Mutation, 17(3), 199–209.

    Article  PubMed  Google Scholar 

  • Barth, B. M., Cabot, M. C., & Kester, M. (2011). Ceramide-based therapeutics for the treatment of cancer. Anti-Cancer Agents in Medicinal Chemistry, 11(9), 911–919.

    Article  CAS  PubMed  Google Scholar 

  • Barth, B. M., Gustafson, S. J., Hankins, J. L., Kaiser, J. M., Haakenson, J. K., Kester, M., et al. (2012b). Ceramide kinase regulates TNFα-stimulated NADPH oxidase activity and eicosanoid biosynthesis in neuroblastoma cells. Cellular Signaling, 24(6), 1126–1133.

    Article  CAS  Google Scholar 

  • Barth, B. M., Gustafson, S. J., & Kuhn, T. B. (2012a). Neutral sphingomyelinase activation precedes NADPH oxidase-dependent damage in neurons exposed to the proinflammatory cytokine tumor necrosis factor-α. Journal of Neuroscience Research, 90(1), 229–242.

    Article  CAS  PubMed  Google Scholar 

  • Barth, B. M., Gustafson, S. J., Young, M. M., Fox, T. E., Shanmugavelandy, S. S., Kaiser, J. M., et al. (2010). Inhibition of NADPH oxidase by glucosylceramide confers chemoresistance. Cancer Biology and Therapy, 10(11), 1126–1136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barth, B. M., Shanmugavelandy, S. S., Kaiser, J. M., McGovern, C., Altınoğlu, E. İ, Haakenson, J. K., et al. (2013). PhotoImmunoNanoTherapy reveals an anticancer role for sphingosine kinase 2 and dihydrosphingosine-1-phosphate. ACS Nano, 7(3), 2132–2144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barth, B. M., Stewart-Smeets, S., & Kuhn, T. B. (2009). Proinflammatory cytokines provoke oxidative damage to actin in neuronal cells mediated by Rac1 and NADPH oxidase. Molecular and Cellular Neuroscience, 41(2), 274–285.

    Article  CAS  PubMed  Google Scholar 

  • Becker, K. A., Uerschels, A. K., Goins, L., Doolen, S., McQuerry, K. J., Bielawski, J., et al. (2020). Role of 1-Deoxysphingolipids in docetaxel neurotoxicity. Journal of Neurochemistry, 154(6), 662–672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bedard, K., & Krause, K.-H. (2007). The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiology Reviews, 87(1), 245–313.

    Article  CAS  Google Scholar 

  • Bejaoui, K., Uchida, Y., Yasuda, S., Ho, M., Nishijima, M., Brown, R. H., et al. (2002). Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis. The Journal of Clinical Investigation, 110(9), 1301–1308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bembi, B., Marchetti, F., Guerci, V. I., Ciana, G., Addobbati, R., Grasso, D., et al. (2006). Substrate reduction therapy in the infantile form of Tay-Sachs disease. Neurology, 66(2), 278–280.

    Article  CAS  PubMed  Google Scholar 

  • Biancini, G. B., Vanzin, C. S., Rodrigues, D. B., Deon, M., Ribas, G. S., Barschak, A. G., et al. (2012). Globotriaosylceramide is correlated with oxidative stress and inflammation in Fabry patients treated with enzyme replacement therapy. Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, 1822(2), 226–232.

    Article  CAS  Google Scholar 

  • Bickert, A., Ginkel, C., Kol, M., Vom Dorp, K., Jastrow, H., Degen, J., et al. (2015). Functional characterization of enzymes catalyzing ceramide phosphoethanolamine biosynthesis in mice. Journal of Lipid Research, 56(4), 821–835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blaho, V. A., Galvani, S., Engelbrecht, E., Liu, C., Swendeman, S. L., Kono, M., et al. (2015). HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature, 523(7560), 342–346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blomqvist, M., Borén, J., Zetterberg, H., Blennow, K., Månsson, J. E., & Ståhlman, M. (2017). High-throughput analysis of sulfatides in cerebrospinal fluid using automated extraction and UPLC-MS/MS. Journal of Lipid Research, 58(7), 1482–1489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bode, H., Bourquin, F., Suriyanarayanan, S., Wei, Y., Alecu, I., Othman, A., et al. (2016). HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship. Human Molecular Genetics, 25(5), 853–865.

    Article  CAS  PubMed  Google Scholar 

  • Boudker, O., & Futerman, A. H. (1993). Detection and characterization of ceramide-1-phosphate phosphatase activity in rat liver plasma membrane. Journal of Biological Chemistry, 268(29), 22150–22155.

    Article  CAS  PubMed  Google Scholar 

  • Breiden, B., & Sandhoff, K. (2020). Mechanism of secondary ganglioside and lipid accumulation in Lysosomal disease. International Journal of Molecular Sciences, 21(7), 2566.

    Article  CAS  PubMed Central  Google Scholar 

  • Brekk, O. R., Korecka, J. A., Crapart, C. C., Huebecker, M., MacBain, Z. K., Rosenthal, S. A., et al. (2020). Upregulating β-hexosaminidase activity in rodents prevents α-synuclein lipid associations and protects dopaminergic neurons from α-synuclein-mediated neurotoxicity. Acta Neuropathologica Communications, 8(1), 127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bright, F., Werry, E. L., Dobson-Stone, C., Piguet, O., Ittner, L. M., Halliday, G. M., et al. (2019). Neuroinflammation in frontotemporal dementia. Nature Reviews Neurology, 15(9), 540–555.

    Article  PubMed  Google Scholar 

  • Brinkmann, V., Davis, M. D., Heise, C. E., Albert, R., Cottens, S., Hof, R., et al. (2002). The immune modulator FTY720 targets sphingosine 1-phosphate receptors. Journal of Biological Chemistry, 277(24), 21453–21457.

    Article  CAS  PubMed  Google Scholar 

  • Brück, W. (2005). The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage. Journal of neurology, 252(5), v3–v9.

    Article  PubMed  CAS  Google Scholar 

  • Cabukusta, B., Nettebrock, N. T., Kol, M., Hilderink, A., Tafesse, F. G., & Holthuis, J. (2017). Ceramide phosphoethanolamine synthase SMSr is a target of caspase-6 during apoptotic cell death. Bioscience Reports, 37(4), 20170867.

    Article  CAS  Google Scholar 

  • Chen, H., Chan, A. Y., Stone, D. U., & Mandal, N. A. (2014). Beyond the cherry-red spot: Ocular manifestations of sphingolipid-mediated neurodegenerative and inflammatory disorders. Survey of Ophthalmology, 59(1), 64–76.

    Article  PubMed  Google Scholar 

  • Cheng, H., Wang, M., Li, J. L., Cairns, N. J., & Han, X. (2013). Specific changes of sulfatide levels in individuals with pre-clinical Alzheimer’s disease: An early event in disease pathogenesis. Journal of Neurochemistry, 127(6), 733–738.

    Article  CAS  PubMed  Google Scholar 

  • Choi, S. H., Aid, S., Kim, H. W., Jackson, S. H., & Bosetti, F. (2012). Inhibition of NADPH oxidase promotes alternative and anti-inflammatory microglial activation during neuroinflammation. Journal of Neurochemistry, 120(2), 292–301.

    Article  CAS  PubMed  Google Scholar 

  • Cologna, S. M., Cluzeau, C. V., Yanjanin, N. M., Blank, P. S., Dail, M. K., Siebel, S., et al. (2014). Human and mouse neuroinflammation markers in Niemann-Pick disease, type C1. Journal of Inherited Metabolic Disease, 37(1), 83–92.

    Article  CAS  PubMed  Google Scholar 

  • Constantin, G., Laudanna, C., Baron, P., & Berton, G. (1994). Sulfatides trigger cytokine gene expression and secretion in human monocytes. FEBS Letters, 350(1), 66–70.

    Article  CAS  PubMed  Google Scholar 

  • Cristóvão, A. C., Guhathakurta, S., Bok, E., Je, G., Yoo, S. D., Choi, D. H., & Kim, Y. S. (2012). NADPH oxidase 1 mediates α-synucleinopathy in Parkinson’s disease. Journal of Neuroscience, 32(42), 14465–14477.

    Article  PubMed  CAS  Google Scholar 

  • Cutler, R. G., Pedersen, W. A., Camandola, S., Rothstein, J. D., & Mattson, M. P. (2002). Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress–induced death of motor neurons in amyotrophic lateral sclerosis. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society, 52(4), 448–457.

    Article  CAS  Google Scholar 

  • Czubowicz, K., Jęśko, H., Wencel, P., Lukiw, W. J., & Strosznajder, R. P. (2019). The role of ceramide and sphingosine-1-phosphate in Alzheimer’s disease and other neurodegenerative disorders. Molecular Neurobiology, 56(8), 5436–5455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • D’Angelo, G., Capasso, S., Sticco, L., & Russo, D. (2013). Glycosphingolipids: Synthesis and functions. The FEBS Journal, 280(24), 6338–6353.

    Article  PubMed  CAS  Google Scholar 

  • De Wit, N. M., den Hoedt, S., Martinez-Martinez, P., Rozemuller, A. J., Mulder, M. T., & de Vries, H. E. (2019). Astrocytic ceramide as possible indicator of neuroinflammation. Journal of Neuroinflammation, 16(48), 1–11.

    Google Scholar 

  • Di Pardo, A., Amico, E., Basit, A., Armirotti, A., Joshi, P., Neely, M. D., & Pepe, G. (2017a). Defective sphingosine-1-phosphate metabolism is a druggable target in Huntington’s disease. Scientific Reports, 7(1), 1–14.

    Article  CAS  Google Scholar 

  • Di Pardo, A., Basit, A., Armirotti, A., Amico, E., Castaldo, S., Pepe, G., et al. (2017b). De novo synthesis of sphingolipids is defective in experimental models of Huntington’s disease. Frontiers in Neuroscience, 11, 698.

    Article  PubMed  PubMed Central  Google Scholar 

  • Di Pardo, A., Castaldo, S., Amico, E., Pepe, G., Marracino, F., Capocci, L., et al. (2018). Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood–brain barrier integrity and exerts therapeutic effect in an animal model of Huntington’s disease. Human Molecular Genetics, 27(14), 2490–2501.

    Article  PubMed  CAS  Google Scholar 

  • Ding, G., Sonoda, H., Yu, H., Kajimoto, T., Goparaju, S. K., Jahangeer, S., et al. (2007). Protein kinase D-mediated phosphorylation and nuclear export of sphingosine kinase 2. Journal of Biological Chemistry, 282(37), 27493–27502.

    Article  CAS  PubMed  Google Scholar 

  • Dinkins, M. B., Enasko, J., Hernandez, C., Wang, G., Kong, J., Helwa, I., et al. (2016). Neutral Sphingomyelinase-2 deficiency ameliorates Alzheimer’s disease pathology and improves cognition in the 5XFAD mouse. Journal of Neuroscience, 36(33), 8653–8667.

    Article  CAS  PubMed  Google Scholar 

  • Diop, F., Vial, T., Ferraris, P., Wichit, S., Bengue, M., Hamel, R., et al. (2018). Zika virus infection modulates the metabolomic profile of microglial cells. PLoS ONE, 13(10), e0206093.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dodge, J. C., Clarke, J., Treleaven, C. M., Taksir, T. V., Griffiths, D. A., Yang, W., et al. (2009). Intracerebroventricular infusion of acid sphingomyelinase corrects CNS manifestations in a mouse model of Niemann-Pick A disease. Experimental Neurology, 215(2), 349–357.

    Article  CAS  PubMed  Google Scholar 

  • Dodge, J. C., Treleaven, C. M., Pacheco, J., Cooper, S., Bao, C., Abraham, M., et al. (2015). Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences, 112(26), 8100–8105.

    Article  CAS  Google Scholar 

  • Dohrn, M. F., Othman, A., Hirshman, S. K., Bode, H., Alecu, I., Fähndrich, E., et al. (2015). Elevation of plasma 1-deoxy-sphingolipids in type 2 diabetes mellitus: A susceptibility to neuropathy? European Journal of Neurology, 22(5), 806-e55.

    Article  CAS  PubMed  Google Scholar 

  • Dominguez, G., Maddelein, M. L., Pucelle, M., Nicaise, Y., Maurage, C. A., Duyckaerts, C., et al. (2018). Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer’s disease brain. Acta Neuropathologica Communications, 6(1), 25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dworski, S., Lu, P., Khan, A., Maranda, B., Mitchell, J. J., Parini, R., et al. (2017). Acid ceramidase deficiency is characterized by a unique plasma cytokine and ceramide profile that is altered by therapy. Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, 1863(2), 386–394.

    Article  CAS  Google Scholar 

  • Eichler, F., & Van Haren, K. (2007). Immune response in leukodystrophies. Pediatric Neurology, 37(4), 235–244.

    Article  PubMed  Google Scholar 

  • Ernst, D., Murphy, S. M., Sathiyanadan, K., Wei, Y., Othman, A., Laurá, M., et al. (2015). Novel HSAN1 mutation in serine palmitoyltransferase resides at a putative phosphorylation site that is involved in regulating substrate specificity. Neuromolecular Medicine, 17(1), 47–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farfel-Becker, T., Vitner, E. B., Kelly, S. L., Bame, J. R., Duan, J., Shinder, V., et al. (2014). Neuronal accumulation of glucosylceramide in a mouse model of neuronopathic Gaucher disease leads to neurodegeneration. Human Molecular Genetics, 23(4), 843–854.

    Article  CAS  PubMed  Google Scholar 

  • Farrell, D. F., & McKhann, G. M. (1971). Characterization of cerebroside sulfotransferase from rat brain. Journal of Biological Chemistry, 246(15), 4694–4702.

    Article  CAS  PubMed  Google Scholar 

  • Figuera-Losada, M., Stathis, M., Dorskind, J. M., Thomas, A. G., Bandaru, V. V. R., Yoo, S. W., et al. (2015). Cambinol, a novel inhibitor of neutral sphingomyelinase 2 shows neuroprotective properties. PLoS ONE, 10(5), 1–18.

    Article  CAS  Google Scholar 

  • Fox, T. E., Houck, K. L., O’Neill, S. M., Nagarajan, M., Stover, T. C., Pomianowski, P. T., et al. (2007). Ceramide recruits and activates protein kinase C ζ (PKCζ) within structured membrane microdomains. Journal of Biological Chemistry, 282(17), 12450–12457.

    Article  CAS  PubMed  Google Scholar 

  • Frey, R. S., Rahman, A., Kefer, J. C., Minshall, R. D., & Malik, A. B. (2002). PKCζ regulates TNF-α–induced activation of NADPH oxidase in endothelial cells. Circulation Research, 90(9), 1012–1019.

    Article  CAS  PubMed  Google Scholar 

  • Furukawa, K., Ohmi, Y., Ji, S., Zhang, P., Bhuiyan, R. H., Ohkawa, Y., et al. (2017). Glycolipids: Essential regulator of neuro-inflammation, metabolism and gliomagenesis. Biochimica et Biophysica Acta BBA, 1861(10), 2479–2484.

    Article  CAS  Google Scholar 

  • Gault, C. R., Obeid, L. M., & Hannun, Y. A. (2010). An overview of sphingolipid metabolism: From synthesis to breakdown. Sphingolipids as signaling and regulatory molecules. New York, NY: Springer.

    Google Scholar 

  • Germain, D. P. (2010). Fabry disease. Orphanet Journal of Rare Diseases, 5(1), 30.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gill, J. S., & Windebank, A. J. (2000). Ceramide initiates NFκB-mediated caspase activation in neuronal apoptosis. Neurobiology of Disease, 7(4), 448–461.

    Article  CAS  PubMed  Google Scholar 

  • Giri, S., Khan, M., Rattan, R., Singh, I., & Singh, A. K. (2006). Krabbe disease: Psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death. Journal of Lipid Research, 47(7), 1478–1492.

    Article  CAS  PubMed  Google Scholar 

  • Gómez-Muñoz, A. (2006). Ceramide 1-phosphate/ceramide, a switch between life and death. Biochimica Biophysica Acta, 1758(12), 2049–2056.

    Article  CAS  Google Scholar 

  • Grimm, M. O., Grimm, H. S., Pätzold, A. J., Zinser, E. G., Halonen, R., Duering, M., et al. (2005). Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin. Nature Cell Biology, 7(11), 1118–1123.

    Article  CAS  PubMed  Google Scholar 

  • Gustafson, S. J., Barth, B. M., McGill, C. M., Clausen, T. P., & Kuhn, T. B. (2007). Wild Alaskan blueberry extracts inhibit a magnesium-dependent sphingomyelinase activity in neurons exposed to TNFα. Current Topics in Nutraceutical Research, 5(4), 183–188.

    CAS  Google Scholar 

  • Gustafson, S. J., Dunlap, K. L., McGill, C. M., & Kuhn, T. B. (2012). A nonpolar blueberry fraction blunts NADPH oxidase activation in neuronal cells exposed to tumor necrosis factor-α. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2012/768101.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hagen, N., Van Veldhoven, P. P., Proia, R. L., Park, H., Merrill, A. H., & van Echten-Deckert, G. (2009). Subcellular origin of sphingosine 1-phosphate is essential for its toxic effect in lyase-deficient neurons. Journal of Biological Chemistry, 284(17), 11346–11353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hait, N. C., Allegood, J., Maceyka, M., Strub, G. M., Harikumar, K. B., Singh, S. K., et al. (2009). Regulation of histone acetylation in the nucleus by sphingosine-1 phosphate. Science, 325(5945), 1254–1257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hannun, Y. A., & Obeid, L. M. (2018). Sphingolipids and their metabolism in physiology and disease. Nature Reviews Molecular Cell Biology, 19(3), 175–191.

    Article  CAS  PubMed  Google Scholar 

  • Henriques, A., Croixmarie, V., Bouscary, A., Mosbach, A., Keime, C., Boursier-Neyret, C., et al. (2018). Sphingolipid metabolism is dysregulated at transcriptomic and metabolic levels in the spinal cord of an animal model of amyotrophic lateral sclerosis. Frontiers in Molecular Neuroscience, 10, 433.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Herr, D. R., Reolo, M. J., Peh, Y. X., Wang, W., Lee, C. W., Rivera, R., et al. (2016). Sphingosine-1-phosphate receptor 2 (S1P2) attenuates reactive oxygen species formation and inhibits cell death: Implications for otoprotective therapy. Scientific Reports, 6, 24541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirabayashi, Y., Igarashi, Y., & Merrill, A. J. (2006). Sphingolipid biology. New York, NY: Springer Science & Business Media.

    Book  Google Scholar 

  • Hou, L., Sun, F., Huang, R., Sun, W., Zhang, D., & Wang, Q. (2019). Inhibition of NADPH oxidase by apocynin prevents learning and memory deficits in a mouse Parkinson’s disease model. Redox Biology, 22, 101134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang, Y., Li, Y., Zhang, H., Zhao, R., Jing, R., Xu, Y., et al. (2018). Zika virus propagation and release in human fetal astrocytes can be suppressed by neutral sphingomyelinase-2 inhibitor GW4869. Cell Discovery, 4(19), 1–16.

    Google Scholar 

  • Ilyas, A. A., Chen, Z. W., & Cook, S. D. (2003). Antibodies to sulfatide in cerebrospinal fluid of patients with multiple sclerosis. Journal of Neuroimmunology, 139(1–2), 76–80.

    Article  CAS  PubMed  Google Scholar 

  • Imarisio, S., Carmichael, J., Korolchuk, V., Chen, C. W., Saiki, S., Rose, C., et al. (2008). Huntington’s disease: From pathology and genetics to potential therapies. Biochemical Journal, 412(2), 191–209.

    Article  CAS  PubMed  Google Scholar 

  • Jackman, N., Ishii, A., & Bansal, R. (2009). Oligodendrocyte development and myelin biogenesis: Parsing out the roles of glycosphingolipids. Physiology, 24(5), 290–297.

    Article  CAS  PubMed  Google Scholar 

  • Jana, A., & Pahan, K. (2004). Human immunodeficiency virus type 1 gp120 induces apoptosis in human primary neurons through redox-regulated activation of neutral sphingomyelinase. Journal of Neuroscience, 24(43), 9531–9540.

    Article  CAS  PubMed  Google Scholar 

  • Jana, A., & Pahan, K. (2010). Sphingolipids in multiple sclerosis. Neuromolecular Medicine, 12(4), 351–361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jana, M., Palencia, C. A., & Pahan, K. (2008). Fibrillar amyloid-β peptides activate microglia via TLR2: Implications for Alzheimer’s disease. The Journal of Immunology, 181(10), 7254–7262.

    Article  CAS  PubMed  Google Scholar 

  • Jazvinšćak Jembrek, M., Hof, P. R., & Šimić, G. (2015). Ceramides in Alzheimer’s disease: Key mediators of neuronal apoptosis induced by oxidative stress and Aβ accumulation. Oxidative Medicine and Cellular Longevity, 2015, 1–17.

    Article  Google Scholar 

  • Jennemann, R., Sandhoff, R., Wang, S., Kiss, E., Gretz, N., Zuliani, C., et al. (2005). Cell-specific deletion of glucosylceramide synthase in brain leads to severe neural defects after birth. Proceedings of the National Academy of Sciences, 102(35), 12459–12464.

    Article  CAS  Google Scholar 

  • Jeon, S. B., Yoon, H. J., Park, S. H., Kim, I. H., & Park, E. J. (2008). Sulfatide, a major lipid component of myelin sheath, activates inflammatory responses as an endogenous stimulator in brain-resident immune cells. The Journal of Immunology, 181(11), 8077–8087.

    Article  CAS  PubMed  Google Scholar 

  • Jeong, Y. H., Kim, Y., Song, H., Chung, Y. S., Park, S. B., & Kim, H. S. (2014). Anti-inflammatory effects of α-galactosylceramide analogs in activated microglia: Involvement of the p38 MAPK signaling pathway. PLoS ONE, 9(2), e87030.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jęśko, H., Wencel, P. L., Wójtowicz, S., Strosznajder, J., Lukiw, W. J., & Strosznajder, R. P. (2020). Fingolimod affects transcription of genes encoding enzymes of ceramide metabolism in animal model of Alzheimer’s disease. Molecular Neurobiology, 57(6), 2799.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jin, S., Zhou, F., Katirai, F., & Li, P. L. (2011). Lipid raft redox signaling: Molecular mechanisms in health and disease. Antioxidants & Redox Signaling, 15(4), 1043–1083.

    Article  CAS  Google Scholar 

  • Johnson, K. R., Johnson, K. Y., Becker, K. P., Bielawski, J., Mao, C., & Obeid, L. M. (2003). Role of human sphingosine-1-phosphate phosphatase 1 in the regulation of intra-and extracellular sphingosine-1-phosphate levels and cell viability. Journal of Biological Chemistry, 278(36), 34541–34547.

    Article  CAS  PubMed  Google Scholar 

  • Jung, J. S., Shin, K. O., Lee, Y. M., Shin, J. A., Park, E. M., Jeong, J., et al. (2013). Anti-inflammatory mechanism of exogenous C2 ceramide in lipopolysaccharide-stimulated microglia. Biochimica et Biophysica Acta (BBA)—Molecular and Cell Biology of Lipids, 1831(6), 1016–1026.

    CAS  Google Scholar 

  • Karaca, I., Tamboli, I. Y., Glebov, K., Richter, J., Fell, L. H., Grimm, M. O., et al. (2014). Deficiency of sphingosine-1-phosphate lyase impairs lysosomal metabolism of the amyloid precursor protein. Journal of Biological Chemistry, 289(24), 16761–16772.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kataoka, H., Sugahara, K., Shimano, K., Teshima, K., Koyama, M., Fukunari, A., & Chiba, K. (2005). FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cellular & Molecular Immunology, 2(6), 439–448.

    CAS  Google Scholar 

  • Kikumoto, Y., Kai, Y., Morinaga, H., Iga-Murahashi, M., Matsuyama, M., Sasaki, T., et al. (2010). Fabry disease exhibiting recurrent stroke and persistent inflammation. Internal Medicine, 49(20), 2247–2252.

    Article  PubMed  Google Scholar 

  • Kim, O. S., Park, E. J., Joe, E. H., & Jou, I. (2002). JAK-STAT signaling mediates gangliosides-induced inflammatory responses in brain microglial cells. Journal of Biological Chemistry, 277(43), 40594–40601.

    Article  CAS  PubMed  Google Scholar 

  • Kim, S., & Sieburth, D. (2018). Sphingosine kinase activates the mitochondrial unfolded protein response and is targeted to mitochondria by stress. Cell Reports, 24(11), 2932-2945.e4.

    Article  CAS  PubMed  Google Scholar 

  • Kitatani, K., Idkowiak-Baldys, J., & Hannun, Y. A. (2008). The sphingolipid salvage pathway in ceramide metabolism and signaling. Cellular Signaling, 20(6), 1010–1018.

    Article  CAS  Google Scholar 

  • Kleinschnitz, C., Grund, H., Wingler, K., Armitage, M. E., Jones, E., Mittal, M., et al. (2010). Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biology, 8(9), e1000479.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kolter, T., Proia, R. L., & Sandhoff, K. (2002). Combinatorial ganglioside biosynthesis. Journal of Biological Chemistry, 277(29), 25859–25862.

    Article  CAS  PubMed  Google Scholar 

  • Kramer, R., Bielawski, J., Kistner-Griffin, E., Othman, A., Alecu, I., Ernst, D., et al. (2015). Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy. FASEB Journal, 29(11), 4461–4472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuhle, J., Lindberg, R. L. P., Regeniter, A., Mehling, M., Steck, A. J., Kappos, L., & Czaplinski, A. (2009). Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis. European Journal of Neurology, 16(6), 771–774.

    Article  CAS  PubMed  Google Scholar 

  • Kułakowska, A., Żendzian-Piotrowska, M., Baranowski, M., Konończuk, T., Drozdowski, W., Górski, J., & Bucki, R. (2010). Intrathecal increase of sphingosine 1-phosphate at early stage multiple sclerosis. Neuroscience Letters, 477(3), 149–152.

    Article  PubMed  CAS  Google Scholar 

  • Lamour, N. F., Wijesinghe, D. S., Mietla, J. A., Ward, K. E., Stahelin, R. V., & Chalfant, C. E. (2011). Ceramide kinase regulates the production of tumor necrosis factor α (TNFα) via inhibition of TNFα-converting enzyme. Journal of Biological Chemistry, 286(50), 42808–42817.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee, K. D., Chow, W. N., Sato-Bigbee, C., Graf, M. R., Graham, R. S., Colello, R. J., et al. (2009). FTY720 reduces inflammation and promotes functional recovery after spinal cord injury. Journal of Neurotrauma, 26(12), 2335–2344.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee, W. C., Tsoi, Y. K., Troendle, F. J., DeLucia, M. W., Ahmed, Z., Dicky, C. A., et al. (2007). Single-dose intracerebroventricular administration of galactocerebrosidase improves survival in a mouse model of globoid cell leukodystrophy. The FASEB Journal, 21(10), 2520–2527.

    Article  CAS  PubMed  Google Scholar 

  • Lei, M., Teo, J. D., Song, H., McEwen, H. P., Lee, J. Y., Couttas, T. A., et al. (2019). Sphingosine kinase 2 potentiates amyloid deposition but protects against hippocampal volume loss and demyelination in a mouse model of Alzheimer’s disease. Journal of Neuroscience, 39(48), 9645–9659.

    Article  CAS  PubMed  Google Scholar 

  • Leto, T. L., Morand, S., Hurt, D., & Ueyama, T. (2009). Targeting and regulation of reactive oxygen species generation by Nox family NADPH oxidases. Antioxidants & Redox Signaling, 11(10), 2607–2619.

    Article  CAS  Google Scholar 

  • Levade, T., Moser, H. W., Fensom, A. H., Harzer, K., Moser, A. B., & Salvayre, R. (1995). Neurodegenerative course in ceramidase deficiency (Farber disease) correlates with the residual lysosomal ceramide turnover in cultured living patient cells. Journal of the Neurological Sciences, 134(1–2), 108–114.

    Article  CAS  PubMed  Google Scholar 

  • Li, X., Jin, S. J., Su, J., Li, X. X., & Xu, M. (2018). Acid sphingomyelinase down-regulation alleviates vascular endothelial insulin resistance in diabetic rats. Basic & Clinical Pharmacology & Toxicology, 123(6), 645–659.

    Article  CAS  Google Scholar 

  • Li, Z., Hailemariam, T. K., Zhou, H., Li, Y., Duckworth, D. C., Peake, D. A., et al. (2007). Inhibition of sphingomyelin synthase (SMS) affects intracellular sphingomyelin accumulation and plasma membrane lipid organization. Biochimica et Biophysica Acta (BBA)—Molecular and Cell Biology of Lipids, 1771(9), 1186–1194.

    CAS  Google Scholar 

  • Lloyd-Evans, E., Morgan, A. J., He, X., Smith, D. A., Elliot-Smith, E., Sillence, D. J., et al. (2008). Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nature Medicine, 14(11), 1247.

    Article  CAS  PubMed  Google Scholar 

  • Lone, M. A., Santos, S., Alecu, I., Silva, L. C., & Hornemann, T. (2019). 1-Deoxysphingolipids. Biochimica et Biophysica Acta (BBA)—Molecular and Cell Biology of Lipids, 1864(4), 512–521.

    CAS  Google Scholar 

  • Lugrin, J., Ciarlo, E., Santos, A., Grandmaison, G., Dos Santos, I., Le Roy, D., & Roger, T. (2013). The sirtuin inhibitor cambinol impairs MAPK signaling, inhibits inflammatory and innate immune responses and protects from septic shock. Biochimica et Biophysica Acta (BBA)—Molecular Cell Research, 1833(6), 1498–1510.

    Article  CAS  Google Scholar 

  • Maceyka, M., Harikumar, K. B., Milstien, S., & Spiegel, S. (2012). Sphingosine-1-phosphate signaling and its role in disease. Trends in Cell Biology, 22(1), 50–60.

    Article  CAS  PubMed  Google Scholar 

  • Maceyka, M., Sankala, H., Hait, N. C., Le Stunff, H., Liu, H., Toman, R., et al. (2005). SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. Journal of Biological Chemistry, 280(44), 37118–37129.

    Article  CAS  PubMed  Google Scholar 

  • Maglione, V., Marchi, P., Di Pardo, A., Lingrell, S., Horkey, M., Tidmarsh, E., & Sipione, S. (2010). Impaired ganglioside metabolism in Huntington’s disease and neuroprotective role of GM1. Journal of Neuroscience, 30(11), 4072–4080.

    Article  CAS  PubMed  Google Scholar 

  • Marshall, J., Sun, Y., Bangari, D. S., Budman, E., Park, H., Nietupski, J. B., et al. (2016). CNS-accessible inhibitor of glucosylceramide synthase for substrate reduction therapy of neuronopathic Gaucher disease. Molecular Therapy, 24(6), 1019–1029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marshall, M. S., Jakubauskas, B., Bogue, W., Stoskute, M., Hauck, Z., Rue, E., et al. (2018). Analysis of age-related changes in psychosine metabolism in the human brain. PLoS ONE, 13(2), e0193438.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • McCampbell, A., Truong, D., Broom, D. C., Allchorne, A., Gable, K., Cutler, R. G., et al. (2005). Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers as age-dependent neuropathy. Human Molecular Genetics, 14(22), 3507–3521.

    Article  CAS  PubMed  Google Scholar 

  • Miguez, A., Garcia-Diaz Barriga, G., Brito, V., Straccia, M., Giralt, A., Ginés, S., et al. (2015). Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington’s disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation. Human Molecular Genetics, 24(17), 4958–4970.

    Article  CAS  PubMed  Google Scholar 

  • Mitrofanova, A., Mallela, S. K., Ducasa, G. M., Yoo, T. H., Rosenfeld-Gur, E., Zelnik, I. D., et al. (2019). SMPDL3b modulates insulin receptor signaling in diabetic kidney disease. Nature Communications, 10(1), 2692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitsutake, S., Date, T., Yokota, H., Sugiura, M., Kohama, T., & Igarashi, Y. (2012). Ceramide kinase deficiency improves diet-induced obesity and insulin resistance. FEBS Letters, 586(9), 1300–1305.

    Article  CAS  PubMed  Google Scholar 

  • Myerowitz, R. (1997). Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene. Human Mutation, 9(3), 195–208.

    Article  CAS  PubMed  Google Scholar 

  • Neubauer, H. A., Tea, M. N., Zebol, J. R., Gliddon, B. L., Stefanidis, C., Moretti, P. A. B., et al. (2019). Cytoplasmic dynein regulates the subcellular localization of sphingosine kinase 2 to elicit tumor-suppressive functions in glioblastoma. Oncogene, 38(8), 1151–1165.

    Article  CAS  PubMed  Google Scholar 

  • Neumann, J., Bras, J., Deas, E., O’Sullivan, S. S., Parkkinen, L., Lachmann, R. H., et al. (2009). Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain, 132(7), 1783–1794.

    Article  PubMed  PubMed Central  Google Scholar 

  • Newton, J., Hait, N. C., Maceyka, M., Colaco, A., Maczis, M., Wassif, C. A., et al. (2017). FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts. The FASEB Journal, 31(4), 1719–1730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Newton, J., Milstien, S., & Spiegel, S. (2018). Niemann-Pick type C disease: The atypical sphingolipidosis. Advances in Biological Regulation, 70, 82–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Norman, E., Cutler, R. G., Flannery, R., Wang, Y., & Mattson, M. P. (2010). Plasma membrane sphingomyelin hydrolysis increases hippocampal neuron excitability by sphingosine-1-phosphate mediated mechanisms. Journal of Neurochemistry, 114(2), 430–439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Othman, A., Bianchi, R., Alecu, I., Wei, Y., Porretta-Serapiglia, C., Lombardi, R., et al. (2015). Lowering plasma 1-deoxysphingolipids improves neuropathy in diabetic rats. Diabetes, 64(3), 1035–1045.

    Article  CAS  PubMed  Google Scholar 

  • Paciotti, S., Albi, E., Parnetti, L., & Beccari, T. (2020). Lysosomal ceramide metabolism disorders: Implications in Parkinson’s disease. Journal of Clinical Medicine, 9(2), 594.

    Article  CAS  PubMed Central  Google Scholar 

  • Pasqui, A. L., Di Renzo, M., Auteri, A., Federico, G., & Puccetti, L. (2007). Increased TNF-α production by peripheral blood mononuclear cells in patients with Krabbe’s disease: Effect of psychosine. European Journal of Clinical Investigation, 37(9), 742–745.

    Article  CAS  PubMed  Google Scholar 

  • Penno, A., Reilly, M. M., Houlden, H., Laurá, M., Rentsch, K., Niederkofler, V., et al. (2010). Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. Journal of Biological Chemistry, 285(15), 11178–11187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Persidsky, Y., Buttini, M., Limoges, J., Bock, P., & Gendelman, H. E. (1997). An analysis of HIV-1-associated inflammatory products in brain tissue of humans and SCID mice with HIV-1 encephalitis. Journal of Neurovirology, 3(6), 401–416.

    Article  CAS  PubMed  Google Scholar 

  • Pettus, B. J., Bielawska, A., Subramanian, P., Wijesinghe, D. S., Maceyka, M., Leslie, C. C., et al. (2004). Ceramide 1-phosphate is a direct activator of cytosolic phospholipase A2. Journal of Biological Chemistry, 279(12), 11320–11326.

    Article  CAS  PubMed  Google Scholar 

  • Porubsky, S., Jennemann, R., Lehmann, L., & Gröne, H. J. (2014). Depletion of globosides and isoglobosides fully reverts the morphologic phenotype of Fabry disease. Cell and Tissue Research, 358(1), 217–227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Potenza, R. L., De Simone, R., Armida, M., Mazziotti, V., Pèzzola, A., Popoli, P., & Minghetti, L. (2016). Fingolimod: A disease-modifier drug in a mouse model of amyotrophic lateral sclerosis. Neurotherapeutics, 13(4), 918–927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robak, L. A., Jansen, I. E., Van Rooij, J., Uitterlinden, A. G., Kraaij, R., Jankovic, J., et al. (2017). Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease. Brain, 140(12), 3191–3203.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rombach, S. M., Smid, B. E., Bouwman, M. G., Linthorst, G. E., Dijkgraaf, M. G., & Hollak, C. E. (2013). Long term enzyme replacement therapy for Fabry disease: Effectiveness on kidney, heart and brain. Orphanet Journal of Rare Diseases, 8(1), 47.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rothhammer, V., Kenison, J. E., Tjon, E., Takenaka, M. C., de Lima, K. A., Borucki, D. M., et al. (2017). Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proceedings of the National Academy of Sciences, 114(8), 2012–2017.

    Article  CAS  Google Scholar 

  • Schiffmann, R., FitzGibbon, E. J., Harris, C., DeVile, C., Davies, E. H., Abel, L., et al. (2008). Randomized, controlled trial of miglustat in Gaucher’s disease type 3. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society, 64(5), 514–522.

    Article  Google Scholar 

  • Schlotawa, L., Adang, L. A., Radhakrishnan, K., & Ahrens-Nicklas, R. C. (2020). Multiple sulfatase deficiency: A disease comprising mucopolysaccharidosis, sphingolipidosis, and more caused by a defect in posttranslational modification. International Journal of Molecular Sciences, 21(10), 3448.

    Article  CAS  PubMed Central  Google Scholar 

  • Schuchman, E. H., & Desnick, R. J. (2017). Types A and B Niemann-pick disease. Molecular Genetics and Metabolism, 120(1–2), 27–33.

    Article  CAS  PubMed  Google Scholar 

  • Sechi, A., Deroma, L., Dardis, A., Ciana, G., Bertin, N., Concolino, D., et al. (2014). Long term effects of enzyme replacement therapy in an Italian cohort of type 3 Gaucher patients. Molecular Genetics and Metabolism, 113(3), 213–218.

    Article  CAS  PubMed  Google Scholar 

  • Senkal, C. E., Salama, M. F., Snider, A. J., Allopenna, J. J., Rana, N. A., Koller, A., et al. (2017). Ceramide is metabolized to acylceramide and stored in lipid droplets. Cell Metabolism, 25(3), 686–697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Settembre, C., Annunziata, I., Spampanato, C., Zarcone, D., Cobellis, G., Nusco, E., et al. (2007). Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency. Proceedings of the National Academy of Sciences, 104(11), 4506–4511.

    Article  CAS  Google Scholar 

  • Seyfried, T. N., Choi, H., Chevalier, A., Hogan, D., Akgoc, Z., & Schneider, J. S. (2018). Sex-related abnormalities in substantia nigra lipids in Parkinson’s disease. ASN Neuro, 10, 1–10.

    Article  CAS  Google Scholar 

  • Seyrantepe, V., Demir, S. A., Timur, Z. K., Von Gerichten, J., Marsching, C., Erdemli, E., et al. (2018). Murine Sialidase Neu3 facilitates GM2 degradation and bypass in mouse model of Tay-Sachs disease. Experimental Neurology, 299, 26–41.

    Article  CAS  PubMed  Google Scholar 

  • Shanbhogue, P., & Hannun, Y. A. (2020). Exploring the therapeutic landscape of sphingomyelinases. Handbook of Experimental Pharmacology, 259, 19–47.

    Article  CAS  PubMed  Google Scholar 

  • Shinghal, R., Scheller, R. H., & Bajjalieh, S. M. (1993). Ceramide-1-phosphate phosphatase activity in brain. Journal of Neurochemistry, 61(6), 2279–2285.

    Article  CAS  PubMed  Google Scholar 

  • Shukitt-Hale, B., Thangthaeng, N., Miller, M. G., Poulose, S. M., Carey, A. N., & Fisher, D. R. (2019). Blueberries improve neuroinflammation and cognition differentially depending on individual cognitive baseline status. The Journals of Gerontology: Series A, 74(7), 977–983.

    CAS  Google Scholar 

  • Siow, D. L., Anderson, C. D., Berdyshev, E. V., Skobeleva, A., Natarajan, V., Pitson, S. M., et al. (2011). Sphingosine kinase localization in the control of sphingolipid metabolism. Advances in Enzyme Regulation, 51(1), 229–244.

    Article  CAS  PubMed  Google Scholar 

  • Siow, D. L., Anderson, C. D., Berdyshev, E. V., Skobeleva, A., Pitson, S. M., & Wattenberg, B. W. (2010). Intracellular localization of sphingosine kinase 1 alters access to substrate pools but does not affect the degradative fate of sphingosine-1-phosphate. Journal of Lipid Research, 51(9), 2546–2559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sivasubramanian, M., Kanagaraj, N., Dheen, S. T., & Tay, S. S. W. (2015). Sphingosine kinase 2 and sphingosine-1-phosphate promotes mitochondrial function in dopaminergic neurons of mouse model of Parkinson’s disease and in MPP+-treated MN9D cells in vitro. Neuroscience, 290, 636–648.

    Article  CAS  PubMed  Google Scholar 

  • Smith, D., Wallom, K. L., Williams, I. M., Jeyakumar, M., & Platt, F. M. (2009). Beneficial effects of anti-inflammatory therapy in a mouse model of Niemann-Pick disease type C1. Neurobiology of Disease, 36(2), 242–251.

    Article  CAS  PubMed  Google Scholar 

  • Suriyanarayanan, S., Auranen, M., Toppila, J., Paetau, A., Shcherbii, M., Palin, E., et al. (2016). The Variant p.(Arg183Trp) in SPTLC2 causes late-onset hereditary sensory neuropathy. Neuromolecular Medicine, 18(1), 81–90.

    Article  CAS  PubMed  Google Scholar 

  • Tafesse, F. G., Vacaru, A. M., Bosma, E. F., Hermansson, M., Jain, A., Hilderink, A., et al. (2014). Sphingomyelin synthase-related protein SMSr is a suppressor of ceramide-induced mitochondrial apoptosis. Journal of Cell Science, 127(2), 445–454.

    CAS  PubMed  Google Scholar 

  • Takajo, D., Matsumoto, H., Noguchi, T., Nishimura, N., & Nonoyama, S. (2020). New variant mutation of glucosylceramidase beta (GBA) and early enzyme replacement therapy for neuronopathic gaucher disease: A case report and literature review. Iranian Journal of Pediatrics. https://doi.org/10.5812/ijp.98996.

    Article  Google Scholar 

  • Takasugi, N., Sasaki, T., Suzuki, K., Osawa, S., Isshiki, H., Hori, Y., et al. (2011). BACE1 activity is modulated by cell-associated sphingosine-1-phosphate. Journal of Neuroscience, 31(18), 6850–6857.

    Article  CAS  PubMed  Google Scholar 

  • Tappino, B., Biancheri, R., Mort, M., Regis, S., Corsolini, F., Rossi, A., et al. (2010). Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease. Human Mutation, 31(12), E1894–E1914.

    Article  PubMed  PubMed Central  Google Scholar 

  • Trajkovic, K., Hsu, C., Chiantia, S., Rajendran, L., Wenzel, D., Wieland, F., et al. (2008). Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science, 319(5867), 1244–1247.

    Article  CAS  PubMed  Google Scholar 

  • Tsai, H. C., & Han, M. H. (2016). Sphingosine-1-phosphate (S1P) and S1P signaling pathway: therapeutic targets in autoimmunity and inflammation. Drugs, 76(11), 1067–1079.

    Article  PubMed  CAS  Google Scholar 

  • Uemura, S., Go, S., Shishido, F., & Inokuchi, J. I. (2014). Expression machinery of GM4: The excess amounts of GM3/GM4S synthase (ST3GAL5) are necessary for GM4 synthesis in mammalian cells. Glycoconjugate Journal, 31(2), 101–108.

    Article  CAS  PubMed  Google Scholar 

  • Vacaru, A. M., Tafesse, F. G., Ternes, P., Kondylis, V., Hermansson, M., Brouwers, J. F., et al. (2009). Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER. Journal of Cell Biology, 185(6), 1013–1027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van Doorn, R., Van Horssen, J., Verzijl, D., Witte, M., Ronken, E., Van Het Hof, B., et al. (2010). Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia, 58(12), 1465–1476.

    Article  PubMed  Google Scholar 

  • Venkatesan, A., & Benavides, D. R. (2015). Autoimmune encephalitis and its relation to infection. Current Neurology and Neuroscience Reports, 15(3), 1–11.

    Article  CAS  Google Scholar 

  • Villani, M., Subathra, M., Im, Y. B., Choi, Y., Signorelli, P., Del Poeta, M., & Luberto, C. (2008). Sphingomyelin synthases regulate production of diacylglycerol at the Golgi. Biochemical Journal, 414(1), 31–41.

    Article  CAS  PubMed  Google Scholar 

  • Vitner, E. B., Farfel-Becker, T., Eilam, R., Biton, I., & Futerman, A. H. (2012). Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher’s disease. Brain, 135(6), 1724–1735.

    Article  PubMed  Google Scholar 

  • Wang, J., Liu, J., Zhou, R., Ding, X., Zhang, Q., Zhang, C., et al. (2018). Zika virus infected primary microglia impairs NPCs proliferation and differentiation. Biochemical and Biophysical Research Communications, 497(2), 619–625.

    Article  CAS  PubMed  Google Scholar 

  • Wang, Q., Qian, L., Chen, S. H., Chu, C. H., Wilson, B., Oyarzabal, E., et al. (2015). Post-treatment with an ultra-low dose of NADPH oxidase inhibitor diphenyleneiodonium attenuates disease progression in multiple Parkinson’s disease models. Brain, 138(5), 1247–1262.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang, W., Shanmugam, M. K., Xiang, P., Yam, T. Y. A., Kumar, V., Chew, W. S., et al. (2020a). Sphingosine-1-phosphate receptor 2 induces otoprotective responses to cisplatin treatment. Cancers, 12(1), 211.

    Article  PubMed Central  CAS  Google Scholar 

  • Wang, Y., Nakajima, T., Diao, P., Yamada, Y., Nakamura, K., Nakayama, J., et al. (2020b). Polyunsaturated fatty acid deficiency affects sulfatides and other sulfated glycans in lysosomes through autophagy-mediated degradation. The FASEB Journal. https://doi.org/10.1096/fj.202000030RR.

    Article  PubMed  PubMed Central  Google Scholar 

  • Weiner, H. L. (2004). Multiple sclerosis is an inflammatory T-cell–mediated autoimmune disease. Archives of Neurology, 61(10), 1613–1615.

    Article  PubMed  Google Scholar 

  • White, A. J., Wijeyekoon, R. S., Scott, K. M., Gunawardana, N. P., Hayat, S., Solim, I. H., et al. (2018). The peripheral inflammatory response to alpha-synuclein and endotoxin in Parkinson’s disease. Frontiers in Neurology, 9, 946.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wilson, E. R., Kugathasan, U., Abramov, A. Y., Clark, A. J., Bennett, D. L. H., Reilly, M. M., et al. (2018). Hereditary sensory neuropathy type 1-associated deoxysphingolipids cause neurotoxicity, acute calcium handling abnormalities and mitochondrial dysfunction in vitro. Neurobiology of Disease, 117, 1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong, Y. C., & Krainc, D. (2016). Lysosomal trafficking defects link Parkinson’s disease with Gaucher’s disease. Movement Disorders, 31(11), 1610–1618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu, D. C., Ré, D. B., Nagai, M., Ischiropoulos, H., & Przedborski, S. (2006). The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice. Proceedings of the National Academy of Sciences, 103(32), 12132–12137.

    Article  CAS  Google Scholar 

  • Wu, G., Yan, B., Wang, X., Feng, X., Zhang, A., Xu, X., & Dong, H. (2008). Decreased activities of lysosomal acid alpha-D-galactosidase A in the leukocytes of sporadic Parkinson’s disease. Journal of the Neurological Sciences, 271(1–2), 168–173.

    Article  CAS  PubMed  Google Scholar 

  • Wu, Y. P., Mizukami, H., Matsuda, J., Saito, Y., Proia, R. L., & Suzuki, K. (2005). Apoptosis accompanied by up-regulation of TNF-α death pathway genes in the brain of Niemann-Pick type C disease. Molecular Genetics and Metabolism, 84(1), 9–17.

    Article  CAS  PubMed  Google Scholar 

  • Young, M. M., Takahashi, Y., Fox, T. E., Yun, J. K., Kester, M., & Wang, H. G. (2016). Sphingosine kinase 1 cooperates with autophagy to maintain endocytic membrane trafficking. Cell Reports, 17(6), 1532–1545.

    Article  CAS  PubMed  Google Scholar 

  • Zhou, W., Woodson, M., Sherman, M. B., Neelakanta, G., & Sultana, H. (2019). Exosomes mediate Zika virus transmission through SMPD3 neutral sphingomyelinase in cortical neurons. Emerging Microbes & Infections, 8(1), 307–326.

    Article  CAS  Google Scholar 

  • Zunke, F., Moise, A. C., Belur, N. R., Gelyana, E., Stojkovska, I., Dzaferbegovic, H., et al. (2018). Reversible conformational conversion of α-synuclein into toxic assemblies by glucosylceramide. Neuron, 97(1), 92–107.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Support came from the National Institutes for Health and National Cancer Institute through award K22-CA190674 (B.M.B.), as well as the University of New Hampshire Hamel Center for Undergraduate Research.

Author information

Authors and Affiliations

  1. Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, 03824, USA

    Emma J. Arsenault & Brian M. Barth

  2. Department of Chemistry, University of Alaska Anchorage, Anchorage, AK, 99508, USA

    Colin M. McGill

Authors
  1. Emma J. Arsenault
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Colin M. McGill
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brian M. Barth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brian M. Barth.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arsenault, E.J., McGill, C.M. & Barth, B.M. Sphingolipids as Regulators of Neuro-Inflammation and NADPH Oxidase 2. Neuromol Med 23, 25–46 (2021). https://doi.org/10.1007/s12017-021-08646-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-021-08646-2

Keywords

Search

Navigation