Information about fast axonal transport in normal and/or diseased mammalian axons (including human) and the regulation of this process is limited. Until this basic information is established, the physiology and pathophysiology of this phenomenon cannot be fully elucidated. We have an opportunity to obtain new basic information on the nature of fast axonal transport in mammalian axons by interfacing sophisticated microscopy, video, and computer technology with ultra-structural analysis and electron probe techniques.
We aim to: 1) Pursue our findings of an abnormality in the fast anterograde axonal transport in human amyotrophic lateral sclerosis (ALS) axons by testing the hypothesis that axonal sprouting (as seen in ALS and experimentally reproduced in partially denervated muscle in mice) leads to increased peripheral demand on neuronal somata resulting in augmented organelle delivery rates. Concurrently, we will evaluate the retrograde intra-axonal organelle traffic in the partially denervated mouse model. 2) Test the hypothesis that peptides known to augment intra-axonal organelle traffic speeds may produce neurogenic dysfunction by overloading the neuronal metabolic machinery and/or depleting axonal reserves of critical components when administered chronically. We have shown that both in vitro and in vivo parathyroid hormone treatment will increase fast axonal transport. Hyperparathyroidism in humans can produce an ALS-like syndrome with weakness, muscle atrophy, fasciculation, and neurogenic changes on muscle biopsy. The hypothesis will be tested by sequential subcutaneous implantation (over months) of PTH-loaded Alzet osmotic mimipumps in rats. 3). Test the hypothesis that peptide agonists, specifically PTH, and arginine vasopressin (AVP) increase mean fast organelle traffic speed through the regulation of intracellular calcium. This effort will further probe the thus far unexplored question of regulation of fast axonal transport. 4). Develop further a data base on fundamental aspects of fast organelle transport in mammalian axons in asymmetric segments of neurons and in functionally different classes of neurons. We will evaluate fast axonal transport in a) central vs. peripheral branches of rat dorsal root ganglia, b) sensory vs. motor spinal nerve roots, c) central nervous system vs. peripheral nerve axons and d) myelinated vs. unmyelinated axons. These functionally different axon segment and axon types have not been systematically analyzed for potential differences in fast organelle traffic, differences which might provide clues to the selective vulnerability of different axons in different disease states.
