The C-Terminal Domains of NF-H and NF-M Subunits Maintain Axonal Neurofilament Content by Blocking Turnover of the Stationary Neurofilament Network

Authors

Mala V. Rao, Aidong Yuan, Jabbar Campbell, Asok Kumar, Ralph A. Nixon

Abstract

Newly synthesized neurofilaments or protofilaments are incorporated into a highly stable stationary cytoskeleton network as they are transported along axons. Although the heavily phosphorylated carboxyl-terminal tail domains of the heavy and medium neurofilament (NF) subunits have been proposed to contribute to this process and particularly to stability of this
structure, their function is still obscure. Here we show in NF-H/M tail deletion [NF-(H/M)tail(delta) mice that the deletion of both of these domains selectively lowers NF levels 3–6 fold along optic axons without altering either rates of subunit synthesis or the rate of slow axonal transport of NF. Pulse labeling studies carried out over 90 days revealed a significantly faster rate of
disappearance of NF from the stationary NF network of optic axons in NF-(H/M) tail(delta) mice. Faster NF disappearance was accompanied by elevated levels of NF-L proteolytic fragments in NF-(H/M) tail(delta) axons. We conclude that NF-H and NF-M Cterminal domains do not normally regulate NF transport rates as previously proposed, but instead increase the proteolytic
resistance of NF, thereby stabilizing the stationary neurofilament cytoskeleton along axons.