Molecular pathogenesis of peripheral dysmyelination common to laminin-2 deficient muscular dystrophy and leprosy

肌营养不良蛋白(DG)复合体的功能障碍被认为在外周髓鞘功能障碍中发挥作用，这在层粘连蛋白-2缺乏的先天性肌肉萎缩和麻风中都是典型的观察到的。在本研究中，我们试图阐明其分子发病机制，并获得了以下结果。(1)周围神经中DG的表达随着雪旺细胞髓鞘形成的启动而增加。(2)DG表达随周围神经退变而减少，随周围神经再生而增加。(3)发现一种基质金属蛋白酶活性，通过裂解βDG的胞外区，通过DG复合体破坏基膜与细胞膜之间的联系。(4)在麻风分枝杆菌细胞壁中发现了一种新的与哺乳动物30 kDa层粘连蛋白结合蛋白同源的层粘连蛋白结合蛋白LBP30，该蛋白可能介导了该细菌对宿主细胞的感染。(5)获得了功能上与DG复合体相互作用的小窝蛋白-3基因缺陷转基因小鼠。动物表现为严重的肌肉萎缩和肌肉中nNOS活性的异常。(6)福山型先天性肌营养不良症患者肌肉中缺乏180 kDa的细胞外基质蛋白P180。在神经系统中，P180与DG复合体共同定位于脑内的胶质细胞界限基板复合体和周围神经的Schwall细胞外膜。综上所述，这些结果表明，DG复合体的功能障碍参与了神经系统缺陷的分子发病机制，如外周髓鞘功能障碍，其修饰可能是纠正这些异常的有效治疗方法。

Dysfunction of the dystroglycan (DG) complex is presumed to play a role in peripheral dysmyelination which is characteristically observed in both laminin-2 deficient congenital muscular dsytrophy and leprosy. In this study, we attempted to clarify its molecular pathogenesis and obtained the following results. (1) DG expression increased concomittant with the initiation of Schwann cell myelination in peripheral nerve. (2) DG expression decreased with degeneration and increased with regeneration of peripheral nerve. (3) A matrix metalloproteinase activity was identified that disrupts the link between the basal lamina and cell membrane via the DG complex by cleaving the extracellular domain of βDG. (4) A novel laminin-binding protein homologus to mammalian 30 kDa laminin-binding protein LBP30 was identified in the cell wall of Mycobacterium leprae and suspected to mediate host cell infection by the bacteria. (5) A transgenic mice with defects in the gene of caveolin-3 that functionally interacts with the DG complex was generated. The animals displayed a phenotype of severe muscular dsytrophy together with abnormal nNOS activity in muscle. (6) A 180 kDa extracellular matrix protein p180 was deficient in the muscle of Fukuyama type congential muscular dystrophy patients. In the nervous system, p180 was co-localized with the DG complex in the glia limitans basal lamina complex in brain and surrounding Schwall cell outer membrane in peripheral nerve. All together, these results indicate that dysfunction of the DG complex is involved in the molecular pathogenesis of nervous system defects such as peripheral dysmyelination and its modification may be effective as a therapy to correct these abnormalities.