Neurofilament Cross-Bridge – A Structure Associated Specifically with the Neurofilament Among the Intermediate Filament Family

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Abstract

The neurofilament (NF) is a member of the intermediate filament family, which is composed of different proteins but all having the same width, approximately 10 nm diameter. Among intermediate filaments, NFs have unique chemical and structural properties. They are composed of three distinctly different proteins called triplet proteins (NF-L, NF-M, and NF-H) and are constituted morphologically of two distinct domains in vivo: core filaments and cross-bridges laterally interconnecting the core filaments. Core filaments are ∼10 nm thick, and cross-bridges are much thinner, 3–5 nm thick. Cross-bridges are constructed from carboxy-terminal tail domains of NF-M and NF-H. When NFs are isolated in vitro, they are observed to be constructed of core filaments and long projections extending vertically from the core filaments. The projections, 3–5 nm in width, correspond morphologically with the tail domains of NF-M and NF-H and are much longer than cross-bridges, but with similar widths. The projections have ramified meshwork-like profiles, whereas the cross-bridges are smooth and straight; however, the projections are the structural scaffolding of cross-bridges, although the mechanism whereby projections are converted to cross-bridges is unknown. Although the tail domain of NF-H is longer and can be phosphorylated more extensively than that of NF-M, curiously NF-M appears to be more essential to form cross-bridges that are related to orienting core filaments parallel and increasing axonal calibers. However, cross-bridges are still constructed even in the presence of the NF-H tail alone without the NF-M tail, and more importantly, the cross-bridges are almost normal when having a phosphorylation-incompetent NF-M tail and an intact NF-H tail. I still have a question whether the NF-M tail or the NF-H tail is essential for cross-bridge formation but emphasize in this chapter that both tails are involved in the bridge formation and are able to compensate for each other when either protein is absent. In this reciprocity between NF-M and NF-H, phosphorylated tail domains of both proteins would be necessary. That is, normal cross-bridges are not as frequent as in either NF-M or NF-H tail-less mice when compared with wild-type mice expressing both tails, suggesting strongly that both tail domains are necessary for typical cross-bridges. When cross-bridges are not formed in the absence of both NF-M and NF-H tails, core filaments without cross-bridges are irregular in alignment, resulting in the impairment of axonal transport of membrane-bound organelles, even where microtubules are normal in appearance. Although it remains unresolved how projections are converted to cross-bridges, it seems certain that cross-bridges are an essential structure in axons, especially in long projection axons where NFs are extremely numerous. Cross-bridges are critical to enhance resistance of NFs to mechanical stress in elongated, nonrigid axoplasm and also to create a constant space between core filaments for the axonal transport of various organelles and molecules regulated by microtubules and their associated proteins.