Age-related Atrophy of Motor Axons in Mice Deficient in the Mid-sized Neurofilament Subunit

Abstract

Abstract. Neurofilaments are central determinants of the diameter of myelinated axons. It is less clear whether neurofilaments serve other functional roles such as maintaining the structural integrity of axons over time. Here we show that an age-dependent axonal atrophy develops in the lumbar ventral roots of mice with a null mutation in the mid-sized neurofilament subunit (NF-M) but not in animals with a null mutation in the heavy neurofilament subunit (NF-H). Mice with null mutations in both genes develop atrophy in ventral and dorsal roots as well as a hind limb paralysis with aging. The atrophic process is not accompanied by significant axonal loss or anterior horn cell pathology. In the NF-M-null mutant atrophic ventral root, axons show an age-related depletion of neurofilaments and an increased ratio of microtubules/neurofilaments. By contrast, the preserved dorsal root axons of NF-M-null mutant animals do not show a similar depletion of neurofilaments. Thus, the lack of an NF-M subunit renders some axons selectively vulnerable to an age-dependent atrophic process. These studies argue that neurofilaments are necessary for the structural maintenance of some populations of axons during aging and that the NF-M subunit is especially critical.

Neurofilament proteins in neurodegenerative diseases

“…It has been proposed that the heavily phosphorylated NF-H subunit detaches from the transport carrier and resides in the axon for months, whereas less phosphorylated subunits are transported at normal slow axonal transport rates and have a short residence time in the axon [88,89]. Consistent with this hypothesis, studies of complete deletion of NF-H, NF-M or both increase the rate of transport of the remaining NF subunits in mouse sciatic nerves [31][32][33]90]. Moreover, in cultured optic nerve axons, hypophosphorylated NF subunits have been interpreted to undergo axonal transport more rapidly than subunits more extensively phosphorylated at their tail domains [91], and the C-terminal phosphorylation of the NF-H subunit correlates with decreased NF axonal transport velocity [92,93].…”

“…Recent studies using NF-H null mice, or mice transfected with a NF-H tailless mutant, suggest that neither NF-H nor its phosphorylated tail is essential for determining neuronal caliber [71,72]. These studies, together with those using NF-M knockout mice [31,32,73], indicate that NF-M plays a more profound role in regulating the axonal diameter. Moreover, alternation of NF-M and NF-H tail domain phosphorylation is associated with the pathology seen in neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and Alzheimer disease (AD), in which tail domain phosphorylation and NF accumulation occur abnormally in perikarya [74][75][76][77].…”

“…Two independent studies have shown that disruption of NF-M has a more severe effect than disruption of NF-H on the radial growth of large myelinated axons [31][32][33]. The absence of NF-M did not cause any phenotypic changes in mice but caused an increase in NF-H level and its phosphorylation.…”

“…stabilization of the filament network and longitudinal extension [30][31][32][33]. NF-H also contributes to the formation of cross-bridges and may interact with microtubules/microfilaments and other cytoskeletal elements [32][33][34].…”

Axonal Neurofilaments Control Multiple Fiber Properties But Do Not Influence Structure or Spacing of Nodes of Ranvier

“…They assemble from three subunits and bear long sidearms that are highly phosphorylated in myelinated domains (de Waegh et al, 1992;Mata et al, 1992;Garcia et al, 2003;Rao et al, 2003). As demonstrated in multiple animal models with absent or disorganized NFs, they play an essential role in axon radial growth (Cleveland et al 1991;Sakaguchi et al, 1993;Elder et al, 1999;Jacomy et al, 1999). However, because mice null for heavy NF subunit (NFH) achieve normal axonal calibers but conduct action potentials at reduced speeds, NFs control more than the physical dimensions of axons (Kriz et al, 2000).…”