Peripheral Demyelination and Neuropathic Pain Behavior in Periaxin-Deficient Mice

Abstract

The Prx gene in Schwann cells encodes L- and S-periaxin, two abundant PDZ domain proteins thought to have a role in the stabilization of myelin in the peripheral nervous system (PNS). Mice lacking a functional Prx gene assemble compact PNS myelin. However, the sheath is unstable, leading to demyelination and reflex behaviors that are associated with the painful conditions caused by peripheral nerve damage. Older Prx-/- animals display extensive peripheral demyelination and a severe clinical phenotype with mechanical allodynia and thermal hyperalgesia, which can be reversed by intrathecal administration of a selective NMDA receptor antagonist We conclude that the periaxins play an essential role in stabilizing the Schwann cell-axon unit and that the periaxin-deficient mouse will be an important model for studying neuropathic pain in late onset demyelinating disease.

NADPH Oxidase-4 Maintains Neuropathic Pain after Peripheral Nerve Injury

“…In particular, the myelin degradation of A␤ afferents promotes susceptibility of their axonal plasma membrane to pronociceptive stimuli, leading to ectopic depolarization and mechanical allodynia (Kobayashi et al, 2008). Accordingly, neuropathic pain behaviors occurred after experimental demyelination of peripheral or central neurons (Wallace et al, 2003;Inoue et al, 2004;Moalem-Taylor et al, 2007;Zhu et al, 2012) and in mutant mice with aberrant myelination or loss of myelin (Gillespie et al, 2000;Chen et al, 2006). Moreover, neuropathic pain accompanies many demyelinating human diseases, such as Guillain-Barré syndrome, CharcotMarie-Tooth type I disease, and multiple sclerosis (Ueda, 2008).…”

Periaxin mutation causes early-onset but slow-progressive Charcot-Marie-Tooth disease

“…L-periaxin is expressed on the abaxonal surface of myelinated Schwann cells and forms a complex with dystrophin-related protein 2 linking the basal lamina outside the cell to the cytoskeleton within the cell (Scherer et al 1995;Sherman and Brophy 2000;Sherman et al 2001). From experiments with knockout mice, L-periaxin is known to play a significant role in the maintenance and repair of peripheral nerve myelin (Gillespie et al 2000;Williams and Brophy 2002). However, expression of L-periaxin in Schwann cells moves from the nucleus to the adaxonal or periaxonal cytoplasm, then to the abaxonal membrane of myelinating Schwann cells with the maturation of myelin.…”

Regulation of Schwann cell function by the extracellular matrix

“…During PNS development, L-periaxin-deficient mice show focal thickenings, infoldings of internodal myelin, and late-onset demyelination, which is similar to DGnull mice (Gillespie et al, 2000). L-periaxin is required for the formation of the DG-dystrophin-related protein-2 (DG-DRP2) complex and is involved in the link between the ECM and the Schwann cell cytoskeleton (Sherman et al, 2001).…”