Abnormal junctions and permeability of myelin in PMP22-deficient nerves

Jiasong Guo, Leiming Wang, Yang Zhang, Jiawen Wu, Sezgi Arpag, Bo Hu, Beat A. Imhof, Xinxia Tian, Bruce D. Carter, Ueli Suter, Jun Li

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

Objective The peripheral myelin protein-22 (PMP22) gene is associated with the most common types of inherited neuropathies, including hereditary neuropathy with liability to pressure palsies (HNPP) caused by PMP22 deficiency. However, the function of PMP22 has yet to be defined. Our previous study has shown that PMP22 deficiency causes an impaired propagation of nerve action potentials in the absence of demyelination. In the present study, we tested an alternative mechanism relating to myelin permeability. Methods Utilizing Pmp22 +/- mice as a model of HNPP, we evaluated myelin junctions and their permeability using morphological, electrophysiological, and biochemical approaches. Results We show disruption of multiple types of cell junction complexes in peripheral nerve, resulting in increased permeability of myelin and impaired action potential propagation. We further demonstrate that PMP22 interacts with immunoglobulin domain-containing proteins known to regulate tight/adherens junctions and/or transmembrane adhesions, including junctional adhesion molecule-C (JAM-C) and myelin-associated glycoprotein (MAG). Deletion of Jam-c or Mag in mice recapitulates pathology in HNPP. Interpretation Our study reveals a novel mechanism by which PMP22 deficiency affects nerve conduction not through removal of myelin, but through disruption of myelin junctions.

Original languageEnglish (US)
Pages (from-to)255-265
Number of pages11
JournalAnnals of Neurology
Volume75
Issue number2
DOIs
StatePublished - Feb 2014

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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