Neurofilament phosphorylation regulates axonal transport by an indirect mechanism: A merging of opposing hypotheses

Neurofilaments (NFs) are among the most abundant constituents of the axonal cytoskeleton. NFs consist of four subunits, termed NF-H, NF-M and NF-L, corresponding to heavy, medium and light in reference to their molecular mass and α-internexin. Phosphorylation of the C-terminal "sidearms" of NF-H and NF-M regulates the ability of NFs to form a cytoskeletal lattice that supports the mature axon. C-terminal phosphorylation events have classically been considered to regulate NF axonal transport. By contrast, studies demonstrating that NF axonal transport was not accelerated following sidearm deletion provided evidence that phosphorylation does not regulate NF transport. Herein, we demonstrate how comparison of transport and distribution of differentially phosphorylated NFs along axons identify common ground between these hypotheses and may resolve this controversy.