The overall goal of this program project is to study the mechanisms of neural degeneration and survival. Five individual project are included. These provide a multifaceted, yet inter-related set of approaches to understanding how and why cells degenerate in certain nervous system disorders and injuries; these studies also aim in the long term to exploit such knowledge for diagnostic and ameliorative purposes. Project I concerns the mechanisms by which neurotrophic factors (and nerve growth factor in particular) maintain neuronal survival/prevent cell death. Experiments will focus on the role of protein phosphorylation in this process. Project II aims to define the functional roles of two neuronal intermediate filament systems. Possible causal roles of these in neuronal degeneration will be explored and efforts will be made to determine why abnormal accumulations of such filaments are often associated with neurodegenerative conditions. This project will mainly rely on cellular transfection techniques to create both over-abundances and absences of neuronal filament proteins in cultured neuronal and non-neuronal cells. Project III seeks to define interaction of the oligodendrocyte Myelin Associated Glycoprotein (MAG) with a putative MAG receptor on axonal membranes. MAG appears to be a major mediator of brain glial cell: neuron interaction associated with myelinogenesis. As such, the MAG:MAG receptor complex may be a critical element in the degeneration of myelin that occurs following axotomy or metabolic neuronal changes. Project IV deals with the possibility that abnormalities in intracellular Ca metabolism are involved in Alzheimer's disease. Experiments will aim to extend the PI's past observations that fibroblasts cultured from Alzheimer's disease patients have altered levels of ionic calcium and abnormal spreading behavior. Extension will include additional Alzheimer's cases, fibroblasts from patients with other neurological disorders, and more readily available cells such as neutrophils and lymphocytes. Additional studies will concern both the consequences and mechanisms underlying the abnormalities in calcium metabolism. Project V tests the hypothesis that regulation of protein kinase C may be involved in Alzheimer's disease. Properties of the kinase will be assessed in Alzheimer's and control fibroblasts. If any differences are observed, the molecular mechanisms underlying such differences will be investigated by a variety of approaches.
