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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.
Pubmed ID: 27583434 RIS Download
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View all literature mentionsBiomedical technology research center that develops computer-aided, advanced microscopy for the acquisition of structural and functional data in the dimensional range of 1 nm to 100 um, a range encompassing macromolecules, subcellular structures and cells. Novel specimen-staining methods, imaging instrumentsincluding intermediate high-voltage transmission electron microscopes (IVEMs) and high-speed, large-format laser-scanning light microscopesand computational capabilities are available for addressing mesoscale biological microscopy of proteins and macromolecular complexes in their cellular and tissue environments. These technologies are developed to bridge understanding of biological systems between the gross anatomical and molecular scales and to make these technologies broadly available to biomedical researchers. NCMIR provides expertise, infrastructure, technological development, and an environment in which new information about the 3D ultrastructure of tissues, cells, and macromolecular complexes may be accurately and easily obtained and analyzed. NCMIR fulfills its mission through technology development, collaboration, service, training, and dissemination. It aims to develop preparative methods and analytical approaches to 3D microscopy applicable to neurobiology and cell biology, incorporating equipment and implementing software that expand the analysis of 3D structure. The core research activities in the areas of specimen development, instrument development, and software infrastructures maximize the advantages of higher voltage electron microscopy and correlated light microscopies to make ambitious imaging studies across scales routine, and to facilitate the use of resources by biomedical researchers. NCMIR actively recruits outside users who will not only make use of these resources, but who also will drive technology development and receive training.
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