Organizational dynamics, functions, and pathobiological dysfunctions of neurofilaments

Neurofilament phosphorylation has long been considered to regulate their axonal transport rate, and in doing so it provides stability to mature axons. We evaluate the collective evidence to date regarding how neurofilament C-terminal phosphorylation may regulate axonal transport. We present a few suggestions for further experimentation in this area, and expand upon previous models for axonal NF dynamics. We present evidence that the NFs that display extended residence along axons are critically dependent upon the surrounding microtubules, and that simultaneous interaction with multiple microtubule motors provides the architectural force that regulates their distribution. Finally, we address how C-terminal phosphorylation is regionally and temporally regulated by a balance of kinase and phosphatase activities, and how misregulation of this balance might contribute to motor neuron disease.