Axonal Transport of Neurofilaments: A Single Population of Intermittently Moving Polymers

Abstract

Studies on mouse optic nerve have led to the controversial proposal that only a small proportion of neurofilaments are transported in axons and that the majority are deposited into a persistently stationary and extensively cross-linked cytoskeletal network that remains fixed in place for months without movement. We have used computational modeling to address this issue, taking advantage of the wealth of published kinetic and morphometric data available for neurofilaments in the mouse visual system. We show that the transport kinetics and distribution of neurofilaments in mouse optic nerve can all be explained fully by a "stop-and-go" model of neurofilament transport, in which axons contain a single population of neurofilaments that all move stochastically in a rapid, intermittent, and bidirectional manner. Importantly, we find that the transport kinetics are not consistent with deposition of neurofilaments into a persistently stationary phase, and that deposition models cannot account for the observed distribution of neurofilaments along mouse optic nerve axons. Finally, we show that the apparent existence of a stationary neurofilament network in mouse optic nerve is most likely an experimental artifact due to contamination of the neurofilament transport kinetics with cytosolic proteins that move at faster rates. Thus, there is no evidence for the deposition of axonally transported neurofilaments into a persistently stationary neurofilament network in optic nerve axons. We conclude that all of the neurofilaments move and that they do so with a single broad and continuous distribution of average rates that is dictated by their intermittent and stochastic motile behavior.