SLOW AXONAL TRANSPORT AND NEUROPATHY

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The slow transport system is fundamental to the growth, maintenance, and regeneration of nerve axons. The essential features include the binding of neurofilaments and microtubules to a translocating mechanism and the coherent transport of many cytosolic proteins with these cytoskeletal elements. A theoretical model has been published which is in good qualitative agreement with many observations of properties of the slow transport system. The model has been used to explain the speed up of neurofilament transport rates in certain neurotoxicant-induced neuropathies. Further theoretical studies have provided a technique by which one could estimate the in-situ rat constants for the adsorption and desorption of the transported proteins to the transport mechanism. It is proposed to use these theoretical developments to analyze both data in the literature and new data of high quality on the transport of individual proteins being prepared for this purpose by Drs. R. Lasek and P. Cancalon. The information gained from these analyses should provide new insight into the interaction of the various components of the slow transport system with one another. By incorporating these insights and extending the model to include the effects of local deposition and degradation, we expect to be able to understand the mechanisms responsible for determining the shape of the radioactivity profile throughout the axon as a function of time. It is also proposed to extend the model to include multiple neurofilament-neurofilament interactions so that the size of growing neurofilamentous masses can be estimated as they are transported down the axon. This analysis should allow quantitative understanding of the way in which the time and position of the blockage of transport occurs as a function of dose schedule and reactivity of the neurotoxicant.