Intensive investigation of the pathophysiology of axonal transport continues, emphasizing the model and sensory neuropathy induced in rats by systemic treatment with p-bromophenylacetylurea (BPAU). Results obtained during the previous funding period show that BPAU neuropathy is associated with abnormalities in the turnaround and recirculation of endogenous proteins by rapid retrograde transport. These findings are significant because turnaround-defects could cause the distal tubulomembranous axonal lesions that characterize BPAU neuropathy. Furthermore, the turnaround-abnormality occurs before other signs of nerve damage and is commensurate with the severity of the pathology. Current results show that BPAU causes another striking effect in motor nerve cells, namely a marked shortening in the onset of rapid transport. We will test the hypothesis that the shortened transport-onset reflects a disturbance in the processing of particles being assembled for delivery into the axon. Three groups of experiments are planned. First we intend to determine whether the onset-effect is uniquely caused by the neurotoxic ureides related to BPAU and to discover whether the dose-effect is uniquely caused by the neurotoxic ureides related to BPAU and to discover whether the dose-effect relations are compatible with a pathogenic role. These experiments make use of a series of BPAU analogues, locally synthesized for the purpose. The second set of experiments will analyze in detail the effect of BPAU on the kinetics of particle transport and transport-turnaround. This work takes advantages of recent advances in optical methods and image-processing for real-time analysis of particle motion. The third set of experiments will explore the possibility that BPAU treatment leads to detectable changes in the biochemical and immunochemical properties of fast transported organelles. This work involves the application of a set of monoclonal antibodies generated in this laboratory to the surface antigens of intra- axonal organelles from rat nerve. Overall we expect to add significantly to understanding of the pathogenesis of toxicant- induced, dying-back neuropathies.
Showing the most recent 10 out of 21 publications
