This proposal is intended to provide training for the applicant in a research, teaching and clinical program leading to a career in investigative neurology and neurobiology. The proposed work is intended to further our limited understanding of the cell biological mechanisms of neuronal degeneration. The paucity of model systems which can be dynamically manipulated has contributed to the slow progress in this area. Yet the underlying health problems posed by neuronal degeneration, which is the common denominator of diseases such as Alzheimer's disease and Huntington's disease, and even normal senescence, are increasingly affecting the health care system, particularly as the population ages. Because the etiologies of the various human neuronal degenerations are clearly multiple, separate strategies are developed here to describe the cellular and molecular processes leading to neuronal death. The cell biology of the neuronal cytoskeleton and the mechanism of its reorganization in the presence of disrupting agents represents one line of investigation. These experiments are designed to provide information relevant to dementia of the Alzheimer type. Studies are designed to address emerging data which implicate a possible role for calcium in concert with aluminum in the pathogenesis of neurofibrillary degeneration. Beginning with neonatal mouse dorsal root ganglion in culture, we shall test the effects of altered aluminum and calcium in the milieu on neurofilament biochemistry and subcellular organization. Probes of how aluminum is handled by the neuronal membrane are planned. Based upon recent advances from this laboratory in understanding the molecular nature of paired helical filaments, we will attemtp the induction of protein-protein crosslinks in cultured human neurons in the hope of reproducing Alzheimer type filaments in vitro. Ongoing studies in chronically aluminum-intoxicated rabbits of axonal cytoskeletal organization and axonal transport of pulse labeled proteins and cholinergic enzymes will be completed. A second, distinct strategy, included because of the 5-year term of this proposal, is the investigation of the genetically programmed, selective neuronal degeneration in the mutant mouse, Purkinje cell degeneration (pcd). This mutant represents and excellent animal model of a delayed-onset inherited perikaryal degeneration in which one can study initially healthy, functioning neurons that die in a predictable fashion. Explants of the mouse cerebellum will be used to determine if the degeneration is observed in vitro. The effect of factors within the neuronal milieum on the doomed cell populations will be studied.
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