Anthony Brown Lab

In addition to their structural role in axons, neurofilaments are also cargoes of axonal transport, unique among other known cargoes because they are flexible protein polymers, just 10 nm in diameter but many micrometers in length. The polymers move outstretched along microtubule tracks, propelled by microtubule motor proteins, kinesin and dynein. The bouts of movement are fast but the average rate of movement is slow because the filaments spend most of their time pausing, resulting in a “stop and go” motile behavior. Thus the speed of neurofilament transport depends on the time scale of observation.

Kinetic analysis of neurofilament transport suggests that the polymers switch between two distinct kinetic states, which we have termed on and off track. Filaments in the on-track state alternate between bouts of rapid movement and short pauses, whereas filaments in the off-track state pause for long periods without any movement. The on-track pauses may last for seconds or tens of seconds, whereas the off-track pauses may last for an hour or more. The net result is that the filaments spend 98% or more of their time pausing during their journey along the axon, making them the slowest of all known axonally transported cargoes. Most neurofilaments are stationary at any point in time, but over a period of hours they all move.

An intriguing feature of neurofilament movement in axons is that it is bidirectional. Anterograde movements predominate, but a significant fraction of the filaments also move retrogradely. On short time scales most filaments appear to have a preferred direction of motion and sustained reversals are relatively infrequent. However, on long time scales the population moves in a net anterograde direction. The function of neurofilament transport has traditionally been considered to be to deliver these polymers to the axon, but the bidirectional nature of their movement suggests that this cannot be the whole story. We believe that neurofilament transport also functions to align and distribute these polymers along the axon. Thus the motor-driven forces of axonal transport may function as much to organize these polymers as to transport them towards the axon tip.

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