Molecular regulators of nerve conduction — Lessons from inherited neuropathies and rodent genetic models

Abstract

Myelinated nerve fibers are highly compartmentalized. Helically wrapped lipoprotein membranes of myelin are integrated with subsets of proteins specifically in each compartment to shape the physiological behavior of these nerve fibers. With the advance of molecular biology and genetics, many functions of these proteins have been revealed over the past decade. In this review, we will first discuss how action potential propagation has been understood by classical electrophysiological studies. In particular, the discussion will be concentrated on how the geometric dimensions of myelinated nerve fibers (such as internodal length and myelin thickness) may affect nerve conduction velocity. This discussion will then extend into how specific myelin proteins may shape these geometric parameters, thereby regulating action potential propagation. For instance, periaxin may specifically affect the internodal length, but not other parameters. In contrast, neuregulin-1 may affect myelin thickness, but not axon diameter or internodal length. Finally, we will discuss how these basic neurobiological observations can be applied to inherited peripheral nerve diseases.

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

“…1). Schwann cells express only two members of the ErbB family of proteins, ErbB2 and ErbB3 [16, 17]. Because ErbB2 lacks ligand-binding ability and ErbB3 lacks kinase activity, these two proteins require heterodimerization to form a functional receptor.…”

Caveats in the Established Understanding of CMT1A

“…This leaves a group of myelinated nerve fibers that are relatively “homogenous” in their sizes with small diameters. Based on the observations by Erlanger and Gasser,17, 18 nerve fibers with similar sizes would produce similar conduction velocities and explain the uniform slowing.…”

“…This leaves a group of myelinated nerve fibers that are relatively “homogenous” in their sizes with small diameters. Based on the observations by Erlanger and Gasser,17, 18 nerve fibers with similar sizes would produce similar conduction velocities and explain the uniform slowing.We have utilized human skin biopsies to examine segmental demyelination in patients with CMT1A 4, 19. Skin biopsy has its limitations, including a difference of gene expression profile from that in human sural nerves 4.…”

N98S mutation in NEFL gene is dominantly inherited with a phenotype of polyneuropathy and cerebellar atrophy

“…The N98S mutation promotes protein aggregates in the cytoplasm. These aggregates appear to prevent NEFL from transporting to axons [1,4,8]. Indeed, decrease of neurofilament staining in axons was observed in patients with E396K mutation of NEFL that also resulted in cytoplasmic protein aggregates [7].…”

“…It encodes a neuronal protein that serves as a key element in the formation of neurofilaments and, therefore, affects axonal transport and nerve conduction velocity [4,6]. At least 20 missense mutations and a few truncation or frame-shift mutations in NEFL have been reported to cause either axonal CMT2E or dysmyelinating CMT1F (Fig.…”