During the past years, our research has focused on the correlation between specific changes in slow axonal transport and structural alterations of the axons. Thus, in an experimental model of human giant axonal neuropathy, we observed that formation of distal axonal enlargements containing neurofilaments is associated with selective acceleration of neurofilament transport. In the present application, we propose to continue to study the relationships between transport and structural changes of the axon. Further, we plan to explore a metabolic system which was recently shown to play a role in the pathology of neurons. Three projects are proposed. In Project 1 we will use two experimental axonopathies characterized by disruption of the neurofilament-microtubule meshwork and other axonal alterations similar to those present in human giant axonal neuropathy and amyotrophic lateral sclerosis to determine and compare the sites of the neurofilament- microtubule meshwork where these disruptions occur and the protein alterations associated with these disruptions. Project 2 is designed to identify and characterize the transported proteins that are involved in the formation of dystrophic axons, a common lesion in human pathology. Fast anterograde, """"""""turnaround"""""""" and retrograde transports of major individual proteins will be analyzed in two experimental models. Presence and distribution of sugar and sulfate content, glycosylation at axon terminal and organelle location of these proteins, will also be examined. Project 3: Ubiquitin, a protein that plays regulatory roles by conjugating to selected proteins, is increased in neurons in neurodegenerative diseases. In some of these diseases, large amounts of ubiquitin appear to be present in abnormal axons. We propose to a) establish whether free ubiquitin and ubiquitin conjugates are transported in axons, b) identify these conjugates and c) determine whether they increase in abnormal conditions such as heat shock or toxic axonopathies. We anticipate that these studies will provide new and substantial information on the mechanisms responsible for the axonal changes that are associated with human diseases such as giant axonal neuropathy, amyotrophic lateral sclerosis and neuroaxonal dystrophy. The studies on ubiquitin may disclose new perspectives in our understanding of the pathology of the axon.
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