In some patients with polyneuropathy there are IgM monoclonal antibodies (m-proteins) that bind to peripheral nerve myelin and that may cause the neuropathy. These M-proteins bind to carbohydrate determinants that are shared by a number of peripheral nerve glycoproteins, including the myelin-associated glycoprotein (MAG), and two glycolipids in peripheral nerve. We have characterized these two glycolipids from human cauda equina and found that they belong to a new class of glycolipids termed sulfated glucuronyl-glycolipids (SGGLs). Subcellular localization studies of bovine peripheral nerve have demonstrated that they are enriched in the axolemma-enriched fraction, while present in myelin and other glial-related membranes in lower concentrations. In addition, these glycolipids are present in bovine dura master and transformed rat Schwann cells. In this project, we plan to further characterize the antigenic determinant(s) that bind to M-proteins in patients with neuropathy and to develop synthetic analogues of the antigenic epitopes. These analogues could then be used therapeutically to block or remove circulating M-proteins in patients and improve the neuropathy. To better understand the role of these glycolipids in the pathogenesis of this disorder, we plan to immunize animals with SGGLs to induce experimental allergic neuritis (EAN) and to obtain polyclonal antibodies against these peripheral nerve glycolipids. Establishing the EAN model with structurally well-defined glycolipid antigens should be extremely important in affording a direct proof that these antigens can actually cause the neuropathy. The polyclonal antisera will be useful in studying their demyelinating and myelination-inhibiting activities in vitro and in vivo, in developing sensitive assays for quantitating these antigens, and for the immunocytochemical localization of these antigens in the nerve. Once this animal model is established, the pathogenetic mechanisms underlying this disorder can be studied in terms of humoral and cellular immune mechanisms, and T- and B-cell interactions regulating the secretion of M-proteins. The results of this project would therefore be important not only for understanding the pathogenesis and pathophysiology of the demyelinating neuropathy associated with IgM M-proteins and plasma cell dyscrasia, but also for providing vital information on the mechanisms of other autoimmune diseases such as multiple sclerosis, Guillain-Barre syndrome, etc.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology C Study Section (NEUC)
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Virginia Commonwealth University
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Itokazu, Yutaka; Wang, Jing; Yu, Robert K (2018) Gangliosides in Nerve Cell Specification. Prog Mol Biol Transl Sci 156:241-263
Itokazu, Yutaka; Tsai, Yi-Tzang; Yu, Robert K (2017) Epigenetic regulation of ganglioside expression in neural stem cells and neuronal cells. Glycoconj J 34:749-756
Tsai, Yi-Tzang; Itokazu, Yutaka; Yu, Robert K (2016) GM1 Ganglioside is Involved in Epigenetic Activation Loci of Neuronal Cells. Neurochem Res 41:107-15
Yu, Robert K; Usuki, Seigo; Itokazu, Yutaka et al. (2016) Novel GM1 ganglioside-like peptide mimics prevent the association of cholera toxin to human intestinal epithelial cells in vitro. Glycobiology 26:63-73
Koon, Noah A; Itokazu, Yutaka; Yu, Robert K (2015) Ganglioside-Dependent Neural Stem Cell Proliferation in Alzheimer's Disease Model Mice. ASN Neuro 7:
Itokazu, Yutaka; Yu, Robert K (2014) Amyloid ?-peptide 1-42 modulates the proliferation of mouse neural stem cells: upregulation of fucosyltransferase IX and notch signaling. Mol Neurobiol 50:186-96
Usuki, Seigo; O'Brien, Dawn; Rivner, Michael H et al. (2014) A new approach to ELISA-based anti-glycolipid antibody evaluation of highly adhesive serum samples. J Immunol Methods 408:52-63
Parameswaran, Reshmi; Lim, Min; Arutyunyan, Anna et al. (2013) O-acetylated N-acetylneuraminic acid as a novel target for therapy in human pre-B acute lymphoblastic leukemia. J Exp Med 210:805-19
Galban-Horcajo, F; Fitzpatrick, A M; Hutton, A J et al. (2013) Antibodies to heteromeric glycolipid complexes in multifocal motor neuropathy. Eur J Neurol 20:62-70
Wang, Jing; Yu, Robert K (2013) Interaction of ganglioside GD3 with an EGF receptor sustains the self-renewal ability of mouse neural stem cells in vitro. Proc Natl Acad Sci U S A 110:19137-42

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