Gangliosides, a class of sialic acid-containing glycosphingolipids ubiquitous in eukaryotic cells, are highly enriched in the membrane components of the central nervous system (CNS), particularly the nerve terminals. Although these glycolipids have been implicated in the regulation of neurotransmission, cell growth and differentiation, and are involved in the specific interaction with a variety of biological modulators including neurotoxins, interferons, opiates, lymphokines, and glycoprotein hormones, the exact functional role of gangliosides is not known. One goal of this project is to elucidate the basic mechanisms through which biochemical signal transduction across the cell membranes may be mediated by gangliosides. Several different areas of research will be pursued, using protein phosphorylation, a major post-translational modification involved in the regulation of numerous biological processes, as a tool. (1) A novel ganglioside-dependent protein kinase is to be purified to homogeneity from both CNS synaptosomes and myelin. Its physicochemical properties and possible roles in neurotransmission will be characterized and assessed, in conjunction with immunocytochemical studies at the ultrastructural level during development. (2) The molecular mechanism by which gangliosides activate protein kinase C, a pivotal enzyme in numerous metabolic pathways, will be studied together with intracellular distribution of this kinase. These studies should provide further insight on the function of gangliosides and protein kinase C in the nervous system. (3) Involvement of gangliosides and protein phosphorylation in cell growth and differentiation such as myelination and demyelination, synapse formation, oncogenesis and aging will be investigated. (4) The mode of action of neurotoxins, especially those which are known to interact with gangliosides, will be analyzed. New information derived from these investigations should provide better undertanding of neuronal and myelin function at both the molecular and cellular levels.
