This is the second competitive renewal of a multidisciplinary, interdependent research program designed to explore the etiology and pathogenesis of major neurodegenerative disorders. The program is the continuation of productive and collaborative efforts by a group of clinically sensitive basic neuroscientists with a wide variety of investigative skills. These colleagues will focus on four interdependent projects in which natural and synthetic chemical agents are used as defined chemical probes to study molecular and cellular mechanisms underlying the selective degeneration of mammalian neurons and/or axons. Specific focus will be placed on elucidating mechanisms underlying self-limiting and progressive neurogenerative disease models, acrylamide neuropathy, Lathyrism (beta-N-oxalylamino-L-alanine), Amnestic Shellfish Poisoning (domoic acid) and, notably, the cycad-linked and amyloid-associated Western Pacific amyotrophic lateral sclerosis/Parkinsonism-dementia complex. Project I will collect and analyze cycad seed for chemical components with DNA-binding and neuronotoxic properties. Core A will synthesize authentic samples of defined cycad neurotoxins for distribution to colleagues who will study their actions on neuronal excitatory mechanisms (Project II), on axonal transport (III), and on gene expression (IV). Project II will employ neurophysiological, neurochemical and morphological methods to examine in neuronal cultures the relationship between biological toxins, the development of neuronal excitatory amino acid receptors, and the distribution of neuronal damage in human motor-system disorders. Project III is focused on the pathophysiological and neurochemical changes in axonal transport and neuronal perikarya which underly primary axonal degeneration induced in animals by the occupational toxin acrylamide. The projects variously rely on Core A technical services, including chemical synthesis, cell and tissue culture, animal behavior and neuropathology. These experimental investigations complement ongoing studies of humans with idiopathic and toxin-associated neurodegenerative diseases. The organization of this program is based on a continuing and successful philosophy that meaningful understanding of human neurological disease is best achieved with the support of laboratory and field studies. Prevention of neurodegenerative disorders through an understanding of etiology is the long-term goal.
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