The purpose of this application is to elucidate the immunopathogenic role of antiglycosphingolipid (GSL) antibodies in peripheral neuropathies and related neurological disorders and to develop effective therapies for these diseases. In recent years, mounting evidence implicates the involvement of anti-GSL antibodies in the pathogenesis of peripheral neuropathies, such as Guillain-Barr? syndrome (GBS). Potential antigens include a variety of acidic GSLs, such as gangliosides and sulfated glycolipids, and neutral GSLs. These GSLs are most abundant in nervous tissues and represent targets of circulating antibodies and cytotoxic immune cells in patients with these neurological disorders. At present, many questions remain regarding the origin of these antibodies and the pathogenic mechanisms of autoantibodies, particularly related to the invasion of antibodies or immune cells from the circulation to the endoneurial space. Our knowledge of the emergence of autoantibodies against neural antigens is still fragmentary, but such knowledge would be prerequisite in developing strategies for preventing and treating these peripheral neurological disorders. Since there is growing awareness that the anti-GSL antibodies arise as the result of antecedent infection, we hypothesize that anti-GSL antibodies may arise from a variety of glycoconjugate antigens through a molecular mimicry mechanism. These glycoconjugates include bacterial lipopolysaccharides (LPSs) that share carbohydrate epitopes similar to those of GSLs.
Three specific aims will be carried out: (1) To test the hypothesis that there is strong correlation between LPSs, anti-GSLs, and the manisfestation of clinical symptoms, we will isolate pure LPSs from several bacteria and studies their structures and antigenicity. (2) We will test the hypothesis that brain microvascular endothelial-cell (BMEC) surface glycoconjugates provide sites for antibody attack and inflammatory leukocyte attachment, leading to permeability changes prior to the onset of neurological symptoms. (3) We will develop rationale and effective therapeutics for immunemediated peripheral neuropathies by """"""""neutralizing"""""""" autoantibodies with anti-idiotypes and peptide """"""""mimitopes"""""""" that bind to the antibodies. Our ultimate goal is to develop a rational and effective treatment of autoimmune peripheral neuropathies and related neurological disorders. RELATIONSHIP TO PUBLIC HEALTH: Infectious agents can induce severe peripheral neuropathies. Some of these agents can come from food, e.g., chicks. This research is to determine what, why, and how these agents can do it. Based on the knowledge gained, we will test a number of novel strategies for the effective treatment of these disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-M (02))
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Gwinn, Katrina
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Georgia Regents University
Schools of Medicine
United States
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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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