Age-related atrophy of motor axons in mice deficient in the mid-sized neurofilament subunit

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 t hat 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) bu t not in animals with a null mutation in the heavy neurofilament subunit (N F-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 pro cess is not accompanied by significant axonal loss or anterior horn cell pa thology. In the NF-M-null mutant atrophic ventral root, axons show an age-r elated depletion of neurofilaments and an increased ratio of microtubules/n eurofilaments. By contrast, the preserved dorsal root axons of NF-M-null mu tant animals do not show a similar depletion of neurofilaments. Thus, the l ack of an NF-M subunit renders some axons selectively vulnerable to an age- dependent atrophic process. These studies argue that neurofilaments are nec essary for the structural maintenance of some populations of axons during a ging and that the NF-M subunit is especially critical.