The Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Glia. 2019 Oct;67(10):1990-2000. doi: 10.1002/glia.23680. Epub 2019 Jul 24.
Membrane metallo-endopeptidase (MME), also known as neprilysin (NEP), has been of interest for its role in neurodegeneration and pain due to its ability to degrade β-amyloid and substance-P, respectively. In addition to its role in the central nervous system, MME has been reported to be expressed in the peripheral system, specifically in the inner and outer border of myelinating fibers, in the Schmidt-Lantermann cleft and in the paranodes. Recently, mutations of this gene have been associated with Charcot-Marie-Tooth Type 2 (CMT2). Peripheral nerve morphometry in mice lacking MME previously showed minor abnormalities in aged animals in comparison to CMT2 patients. We found that MME expression was dysregulated after nerve injury in a Neuregulin-1 dependent fashion. We therefore explored the hypothesis that MME may have a role in remyelination. In the naïve state in adulthood we did not find any impairment in myelination in MME KO mice. After nerve injury the morphological outcome in MME KO mice was indistinguishable from WT littermates in terms of axon regeneration and remyelination. We did not find any difference in functional motor recovery. There was a significant difference in sensory function, with MME KO mice starting to recover response to mechanical stimuli earlier than WT. The epidermal reinnnervation, however, was unchanged and this altered sensitivity may relate to its known function in cleaving the peptide substance-P, known to sensitise nociceptors. In conclusion, although MME expression is dysregulated after nerve injury in a NRG1-dependent manner this gene is dispensable for axon regeneration and remyelination after injury.
膜金属内肽酶（MME），也称为脑啡肽酶（NEP），因其分别降解β-淀粉样蛋白和 P 物质的能力而引起人们对其在神经退行性变和疼痛中的作用的关注。除了在中枢神经系统中的作用外，据报道 MME 在外周系统中表达，特别是在外周髓鞘纤维的内、外边界、施密特-兰滕曼裂隙和节间区。最近，该基因的突变与 Charcot-Marie-Tooth 型 2（CMT2）有关。先前缺乏 MME 的小鼠的周围神经形态计量学研究表明，与 CMT2 患者相比，老年动物的异常较小。我们发现，神经损伤后，MME 的表达以 Neuregulin-1 依赖的方式失调。因此，我们探讨了 MME 可能在髓鞘再生中发挥作用的假设。在成年的幼稚状态下，我们没有发现 MME KO 小鼠的髓鞘形成有任何缺陷。在神经损伤后，MME KO 小鼠的形态学结果与 WT 同窝仔鼠在轴突再生和髓鞘再生方面没有区别。我们没有发现功能运动恢复有任何差异。感觉功能有显著差异，MME KO 小鼠对机械刺激的反应恢复比 WT 早。然而，表皮再神经支配没有变化，这种改变的敏感性可能与其在切割肽物质 P 方面的已知功能有关，已知物质 P 会使伤害感受器敏感。总之，尽管 MME 的表达在神经损伤后以 NRG1 依赖的方式失调，但该基因对于损伤后的轴突再生和髓鞘再生是可有可无的。
