This project explores the functions of neuronal complex carbohydrates-major molecular determinants on all nerve cells. Recent research provides strong evidence of the specific roles of these molecules in nerve cell regulation, and new tools with which to explore those roles. In particular, an essential role for gangliosides, major nerve cell sialoglycoconjugates, in axon-myelin interactions was recently demonstrated in vitro and in vivo. Specific gangliosides are required for long-term axon-myelin stability and may act as nerve cell receptors for myelin-mediated inhibition of nerve regeneration, a major mechanism limiting nerve repair after ventral nervous system (e.g., spinal cord) injury. This project will capitalize on recent findings, using new experimental tools to investigate the relationship between ganglioside expression and nerve egeneration, to study the effect of targeted sialic acid modification in enhancing nerve regeneration, and to probe the molecular basis for ganglioside-mediated nerve cell regulation. Cell surface carbohydrates regulate nerve regeneration. The nature central nervous system is inhibitory to nerve regeneration, due in part to myelin inhibitor proteins which bind to the nerve cell surface and halt axon outgrowth. One of these proteins, myelin-associated glycoproteins (MAG) is a sialic acid-dependent lectin (carbohydrate binding protein) which targets endogenous nerve cell gangliosides. This project will probe the function of gangliosides in the inhibition of nerve regeneration by modifying ganglioside expression, genetically and biochemically, and testing for enhanced nerve regeneration in vitro and in vivo. Molecular mechanisms of ganglioside-mediated neuronal regulation. Gangliosides reside on the cell membrane in dynamic membrane """"""""rafts""""""""-lateral associations of gangliosides, other sphingolipids, and membrane-associated signaling molecules. This project will use MAG chimeras, anti-ganglioside monoclonal antibodies, and synthetic photoaffinity ganglioside derivatives to search for transmembrane signaling cascades initiated with MAG binds to its target gangliosides to regulate nerve function.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Pathobiochemistry Study Section (PBC)
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Chiu, Arlene Y
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Johns Hopkins University
Schools of Medicine
United States
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Yoo, Seung-Wan; Motari, Mary G; Schnaar, Ronald L (2017) Agenesis of the corpus callosum in Nogo receptor deficient mice. J Comp Neurol 525:291-301
Schnaar, Ronald L (2016) Gangliosides of the Vertebrate Nervous System. J Mol Biol 428:3325-3336
Palandri, A; Salvador, V R; Wojnacki, J et al. (2015) Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75(NTR) receptor-mediated activation of RhoA signaling pathways. Cell Death Dis 6:e1876
Yoo, Seung-Wan; Motari, Mary G; Susuki, Keiichiro et al. (2015) Sialylation regulates brain structure and function. FASEB J 29:3040-53
Schnaar, Ronald L; Gerardy-Schahn, Rita; Hildebrandt, Herbert (2014) Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. Physiol Rev 94:461-518
Prendergast, Jillian; Umanah, George K E; Yoo, Seung-Wan et al. (2014) Ganglioside regulation of AMPA receptor trafficking. J Neurosci 34:13246-58
Vajn, Katarina; Viljeti?, Barbara; Degme?i?, Ivan Ve?eslav et al. (2013) Differential distribution of major brain gangliosides in the adult mouse central nervous system. PLoS One 8:e75720
Sturgill, Elizabeth R; Aoki, Kazuhiro; Lopez, Pablo H H et al. (2012) Biosynthesis of the major brain gangliosides GD1a and GT1b. Glycobiology 22:1289-301
Viljeti?, Barbara; Degmeci?, Ivan Veceslav; Krajina, Vinko et al. (2011) Distribution of major brain gangliosides in olfactory tract of frogs. Coll Antropol 35 Suppl 1:121-6
Zhang, Gang; Lehmann, Helmar C; Manoharan, Sowmia et al. (2011) Anti-ganglioside antibody-mediated activation of RhoA induces inhibition of neurite outgrowth. J Neurosci 31:1664-75

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