Abnormal junctions and permeability of myelin in PMP22-deficient nerves

作者：Guo Jiasong; Wang Leiming; Zhang Yang; Wu Jiawen; Arpag Sezgi; Hu Bo; Imhof Beat A; Tian Xinxia; Carter Bruce D; Suter Ueli; Li Jun^*

来源：Annals of Neurology, 2014, 75(2): 255-265.

DOI：10.1002/ana.24086

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. Ann Neurol 2014;75:255-265

• 出版日期2014-2
• 单位北京大学