Abstract
Schwann cells in the peripheral nervous systems extend their membranes to wrap axons concentrically and form the insulating sheath, called myelin. The spaces between layers of myelin are sealed by myelin junctions. This tight insulation enables rapid conduction of electric impulses (action potentials) through axons. Demyelination (stripping off the insulating sheath) has been widely regarded as one of the most important mechanisms altering the action potential propagation in many neurological diseases. However, the effective nerve conduction is also thought to require a proper myelin seal through myelin junctions such as tight junctions and adherens junctions. In the present study, we have demonstrated the disruption of myelin junctions in a mouse model (Pmp22+/-) of hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of Pmp22 gene. We observed a robust increase of F-actin in Pmp22+/- nerve regions where myelin junctions were disrupted, leading to increased myelin permeability. These abnormalities were present long before segmental demyelination at the late phase of Pmp22+/- mice. Moreover, the increase of F-actin levels correlated with an enhanced activity of p21-activated kinase (PAK1), a molecule known to regulate actin polymerization. Pharmacological inhibition of PAK normalized levels of F-actin, and completely prevented the progression of the myelin junction disruption and nerve conduction failure in Pmp22+/- mice. Our findings explain how abnormal myelin permeability is caused in HNPP, leading to impaired action potential propagation in the absence of demyelination. We call it “functional demyelination”, a novel mechanism upstream to the actual stripping of myelin that is relevant to many demyelinating diseases. This observation also provides a potential therapeutic approach for HNPP.
Highlights
Depolarizing current at the node of Ranvier is typically five times higher than the minimum required to trigger the action potential
We investigated a novel mechanism that impairs nerve conduction without the removal of myelin, called functional demyelination
Our recent study reports that deficiency of PMP22 in hereditary neuropathy with liability to pressure palsies (HNPP) disrupts myelin junctions of Schwann cells that seal the spaces between layers of myelin membrane
Summary
Depolarizing current at the node of Ranvier is typically five times higher than the minimum required to trigger the action potential This surplus is called the “safety factor” [1]. The safety factor is secured by the wrapping of the glial cell membrane around axons to produce the insulating sheath, called myelin. Denuded axons shunt the depolarizing current out of nerve fibers, leading to either a reduction of conduction velocity or complete failure of action potential propagation. The latter is called “conduction block” and produces focal sensory loss and/or limb paralysis [2, 3]
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