Abnormal junctions and permeability of myelin in PMP22-deficient nerves.
Abnormal junctions and permeability of myelin in PMP22-deficient nerves.
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DOI：
10.1002/ana.24086
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发表时间：
2014-02
影响因子：
11.2
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Guo J;Wang L;Zhang Y;Wu J;Arpag S;Hu B;Imhof BA;Tian X;Carter BD;Suter U;Li J
外周髓鞘蛋白22 （PMP22）基因与最常见的遗传性神经病变相关，包括由PMP22缺乏引起的遗传性神经病变伴压性麻痹（HNPP）。然而，PMP22的功能尚未明确。我们之前的研究表明，PMP22缺乏会导致脱髓鞘缺失时神经动作电位的传播受损。在本研究中，我们测试了另一种与髓磷脂通透性相关的机制。利用Pmp22+/−小鼠作为HNPP模型，我们使用形态学、电生理和生化方法评估髓鞘连接及其通透性。我们发现周围神经中多种类型的细胞连接复合物的破坏，导致髓鞘通透性增加和动作电位传播受损。我们进一步证明PMP22与已知的调节紧密/粘附连接和/或跨膜粘附的含免疫球蛋白结构域蛋白相互作用，包括连接粘附分子c （JAM-C）和髓鞘相关糖蛋白（MAG）。小鼠中Jam-c或Mag的缺失再现了HNPP的病理。我们的研究揭示了一种新的机制，通过PMP22缺乏影响神经传导不是通过髓磷脂的去除，而是通过髓磷脂连接的破坏。
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. Utilizing Pmp22+/− mice as a model of HNPP, we evaluated myelin junctions and their permeability using morphological, electrophysiological, and biochemical approaches. 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. Our study reveals a novel mechanism by which PMP22 deficiency affects nerve conduction not through removal of myelin, but through disruption of myelin junctions.