Developments in neurochemistry related to axoplasmic transport.

Fast transport of labeled proteins in vertebrate nerve and the particle movement seen in the axoplasm of giant fibers with video microscopy share basic properties. They are both dependent on oxidative metabolism providing ATP to drive transport with the microtubules acting as the "rails" for transport. Glucose is the usual metabolite but when glucose is deleted from an in vitro medium some other endogenous metabolite(s) present in vertebrate nerve can temporarily provide ATP to carry on transport for several hours. The transport filament hypothesis was proposed to account for fast transport in vertebrate nerve. Carriers were pictured to which the various components transported are bound and these moved along the microtubules with the needed energy supplied by ATP utilized by a calmodulin activated Ca-Mg ATPase. Analogous models based on video visualization of particle movement have been proposed. While these models can in general account for fast transport, we require a better understanding of the wide range of slower and intermediate rates of transport seen in vertebrate nerve. The large component of cytoskeletal proteins moved down as slow component a (SCa) at a rate close to 1 mm/d has been accounted for by two different models. In the Structural Hypothesis the microtubules and neurofilament cytoskeletal organelles are considered to be assembled in the cell bodies and then moved down within the axon as an assembled matrix. In the Unitary Hypothesis the cytoskeletal proteins are moved down as soluble proteins on carriers as in the case of fast transport, but these slow transported proteins are more rapidly dropped off in the axon for turnover in the stationary cytoskeleton. Other slow and intermediate rates can similarly be accounted for on the basis of this one mechanism. Experimental evidence in support of the Unitary Hypothesis is presented based on the use of the beading phenomenon to partition the assembled cytoskeleton from the soluble components. Additional evidence is given for a distal assembly of the cytoskeleton in regenerating fibers which further supports Unitary Hypothesis. The Unitary Hypothesis not only best fits with the known properties of transport, it offers new approaches to an understanding of the action of neurotoxins and the genesis of neuropathological changes.