What is slow axonal transport?

Abstract

While the phenomenon of slow axonal transport is widely agreed upon, its underlying mechanism has been controversial for decades. There is now persuasive evidence that several different mechanisms could contribute to slow axonal transport. Yet proponents of different theories have been hesitant to explicitly integrate what were, at least initially, opposing models. We suggest that slow transport is a multivariate phenomenon that arises through mechanisms that minimally include: molecular motor-based transport of polymers and soluble proteins as multi-protein complexes; diffusion; and en bloc transport of the axonal framework by low velocity transport and towed growth (due to increases in body size). In addition to integrating previously described mechanisms of transport, we further suggest that only a subset of transport modes operate in a given neuron depending on the region, length, species, cell type, and developmental stage. We believe that this multivariate approach to slow axonal transport better explains its complex phenomenology: including its bi-directionality; the differing velocities of transport depending on cargo, as well differing velocities due to anatomy, cell type and developmental stage.

Introduction

Neurons have a remarkable geometry, their axons can extend over the distance of meters and can contain a total volume that is hundreds of times greater than that of the cell body. Because the cell body contains most of the protein-synthesizing capacity, an enormous mass is transported into the axon to build and replace components required for neuronal function.

In the classic studies of axonal transport, a pulse of radio-labeled amino acid was applied to neuronal cell bodies that were then taken up and made into proteins over a time period of a few hours. Then at various intervals ranging from hours to several months the nerve was excised, divided into segments, and run out on protein gels, and the profile of radio-labeled proteins along the nerve was determined either by measuring the amount of radioactivity in each segment or by autoradiography (Fig. 1A). Transport was characterized by the movement of peaks of radio-labeled proteins (Fig. 1B) [1]. The original categorization of axonal transport into “fast” and “slow” components was based on the observation that different types of proteins moved at different velocities. The movement of membrane bound proteins at a rate roughly between 20 and 400 mm/day was called “Fast Axonal Transport”. Where the movement of non-membrane bound proteins at a rate of 0.1–20 mm/day was called “Slow Axonal Transport”. In contrast to the controversy surrounding slow transport, the mechanism of fast transport is now widely agreed to depend on the movement of membranous vesicles on microtubule ‘tracks’ powered by the motor proteins kinesin and dynein.

Classic examples of slow transport in the olfactory neurons of garfish and in the rat sciatic nerve are shown in Fig. 1 [2], [3]. Slow axonal transport has three key features: (1) pulse labeled proteins move in the anterograde direction over the course of days, (2) the labeled proteins were seen to be transported as peaks or waves, and (3) different types of non-membrane bound proteins move at different velocities. The question we raise is “What is Slow Axonal Transport?” We make the argument that slow axonal transport cannot be explained by any single transport mechanism, but instead is a multivariate process.