Internode length is reduced during myelination and remyelination by neurofilament medium phosphorylation in motor axons

Abstract

The distance between nodes of Ranvier, referred to as internode length, positively correlates with axon diameter, and is optimized during development to ensure maximal neuronal conduction velocity. Following myelin loss, internode length is reestablished through remyelination. However, remyelination results in short internode lengths and reduced conduction rates. We analyzed the potential role of neurofilament phosphorylation in regulating internode length during remyelination and myelination. Following ethidium bromide induced demyelination, levels of neurofilament medium (NF-M) and heavy (NF-H) phosphorylation were unaffected. Preventing NF-M lysine-serine-proline (KSP) repeat phosphorylation increased internode length by 30% after remyelination. To further analyze the role of NF-M phosphorylation in regulating internode length, gene replacement was used to produce mice in which all KSP serine residues were replaced with glutamate to mimic constitutive phosphorylation. Mimicking constitutive KSP phosphorylation reduced internode length by 16% during myelination and motor nerve conduction velocity by ~27% without altering sensory nerve structure or function. Our results suggest that NF-M KSP phosphorylation is part of a cooperative mechanism between axons and Schwann cells that together determine internode length, and suggest motor and sensory axons utilize different mechanisms to establish internode length.

Sex Differences in the Effect of Alcohol Drinking on Myelinated Axons in the Anterior Cingulate Cortex of Adolescent Rats

“…Three pieces of evidence support this demyelination + remyelination hypothesis in males: (1) a decrease in overall myelin density, coupled with (2) no change in the number of nodes, and (3) a shift in the distribution towards myelinated axons with larger diameters. All three results are consistent with having thinner and shorter myelin sheaths, which is a staple of remyelination [45,46]. We did not observe the same phenomenon in females, suggesting a less robust effect of alcohol on myelin in females, or possibly a more effective remyelination process that returns the myelinated fiber density levels back to normal by the end of the alcohol exposure period.…”

Targeted neuromodulation of pelvic floor nerves in aging and multiparous rabbits improves continence

“…During motor axon regeneration, re-growing axons are small in diameter, have an even distribution of ion channels in the membrane, and are initially unmyelinated. As remyelination starts and axons mature, ion channels clusters at the node of Ranvier, and conduction velocity increases, albeit less than pre-injury levels due to shorter internodal lengths 31 and ectopic ion channel clustering 36 , 37 . Due to those changes, regenerating motor axons are expected to have higher activation thresholds and slower conduction velocities.…”

“…In addition, it is well established [31][32][33][34][35] that the axon diameter, myelin thickness, and internodal length play a crucial role in axon conduction velocity, and determine electrical stimulation thresholds (i.e., large diameter axons are depolarized first). During motor axon regeneration, re-growing axons are small in diameter, have an even distribution of ion channels in the membrane, and are initially unmyelinated.…”

Much More Than a Scaffold: Cytoskeletal Proteins in Neurological Disorders

“…In addition to its role as a signal for the assembly and organization of NFs within neurons, the phosphorylation of one particular NF subunit, NF-H, has been recently linked to the optimal maintenance of the internode length (the section of the axon between nodes of Ranvier) [50]. A correct internode length is essential to maintain the maximal conduction velocity of peripheral nerves [51,52].…”

“…A correct internode length is essential to maintain the maximal conduction velocity of peripheral nerves [51,52]. The myelin-dependent phosphorylation of the KSP repeats within the C-terminal domain of NF-M is a key step in determining internode length [50]. The phosphorylation of NFs remains a focus of active research because several neurodegenerative disorders have been linked to the disruption of the phosphorylation state of NFs [39] in Alzheimer's Disease [53], Parkinson's Disease [54], Amyotrophic Lateral Sclerosis [55], Multiple Sclerosis [56], and Charcot Marie Tooth [57,58].…”