Neurofibrillary changes are pathological hallmarks of many chronic diseases of the nervous system, including Alzheimer's disease, some cases of amyotrophic lateral sclerosis, and a variety of neurotoxic disorders. The pathogenesis of such neurofilamentous accumulations thus represents a fundamental problem in neuropathology. Previous studies in this project have established the Beta ,Beta'-iminodipropionitrile (IDPN) model as a valuable system for pathogenetic studies and have related the pathological changes -- proximal neurofilamentous swellings and distal atrophy of large axons -- to a selective defect in the slow axonal transport of neurofilaments. The transport defect, in turn, appears to result from a distinctive reorganization in the axonal cytoskeleton. A major hypothesis of the present proposal is that similar alterations in the transport and organization of neurofilaments may underlie other types of neurofibrillary degeneration. The proposed studies utilize axonal transport techniques to assess the transport and disposition of neurofilaments and other cytoskeletal elements in the neurofilamentous neuropathies produced by 2,5-hexanedione (HD), 3,4-dimethyl-2,5-hexanedione (DMHD), and acrylamide (AC) and compare the findings to those produced by IDPN. Our hypothesis is that, in all these disorders, high-dose, short-term toxin administration will reproduce the transport changes, cytoskeletal reorganization, and pathological findings of the IDPN model. Other studies will test the possibility that the extent of axonal breakdown in these various models may correlate with the extent of impairment of fast bidirectional transport in distal axonal regions. Finally, non-neuronal culture systems and antibodies raised against the neurotoxins will be used to explore the intracellular localization and molecular mechanisms of these toxins. Continued systematic exploration of the mechanisms underlying these neurofilamentous axonal disorders will have major implications for understanding the bases for human neurofibrillary degenerations. These studies should also provide insights into the factors involved in normal cytoskeletal organization and transport.
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