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

层粘连蛋白-2缺陷型肌营养不良症和麻风病常见外周髓鞘形成障碍的分子发病机制

• 批准号: 11470151
• 负责人: MATSUMURA Kiichiro
• 金额: $ 8.45万
• 依托单位: Teikyo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470151/
• 关键词: Myelination; Laminin-2 Deficiency; Leprosy; Laminin-2; Dystroglycan; Schwann Cell

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.

糖醛酸异常（DG）复合物的功能障碍被认为在外周髓鞘异常中起作用，这在层粘连蛋白-2缺陷型先天性肌萎缩症和麻风病中都是特征性的。在本研究中，我们试图阐明其分子发病机制，并获得以下结果。(1) DG表达随着周围神经雪旺细胞髓鞘形成的开始而增加。(2) DG表达随周围神经变性而降低，随周围神经再生而升高。(3)发现了一种基质金属蛋白酶活性，通过切割β - DG的胞外结构域，破坏了DG复合物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层粘连蛋白结合蛋白，与哺乳动物30kda层粘连蛋白结合蛋白LBP30同源，可能介导了麻风分枝杆菌对宿主细胞的感染。(5)产生了与DG复合物功能相互作用的caveolin-3基因缺陷转基因小鼠。这些动物表现出严重肌肉萎缩的表型，同时肌肉中nNOS活性异常。(6)福山型先天性肌营养不良患者肌肉中缺乏180kda细胞外基质蛋白p180。在神经系统中，p180与DG复合物共定位于脑内限定胶质细胞基底层复合体和周围神经施沃尔细胞外膜。综上所述，这些结果表明DG复合物的功能障碍参与了神经系统缺陷（如外周髓鞘发育异常）的分子发病机制，其修饰可能是纠正这些异常的有效治疗方法。

项目成果

Masaki, T., Matsumura, K., Hirata, A., Yamada, H., Hase, A., Arai, K., Shimizu, T., Yorifuji, H., Motoyoshi, K. and Kamakura, K.: "Expression of dystroglycan and the Iaminin-α2 chain in the rat peripheral nerve during development."Exp. Neurol. 174. 109-11

Masaki, T.、Matsumura, K.、Hirata, A.、Yamada, H.、Hase, A.、Arai, K.、Shimizu, T.、Yorifuji, H.、Motoyoshi, K. 和 Kamakura, K.： “发育过程中大鼠周围神经中肌营养不良聚糖和层粘连蛋白-α2 链的表达。”Exp. 174. 109-11

Sunada, Y., et al.: "Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity."Hum.Molec.Genet.. 10. 173-178 (2001)

Sunada, Y., 等人：“表达突变型 Caveolin-3 的转基因小鼠表现出与 nNOS 活性增加相关的严重肌病。”Hum.Molec.Genet.. 10. 173-178 (2001)

Masaki, T., et al.: "Expression of dystroglycan and the laminin-α2 chain in the rat peripheral nerve during development"Exp.Neurol.. 174. 109-117 (2002)

Masaki, T., et al.：“发育过程中大鼠周围神经中肌营养不良聚糖和层粘连蛋白-α2 链的表达”Exp.Neurol.. 174. 109-117 (2002)

Masaki T et al.: "Expression of dystroglycan and the laminin-α2 chain in the rat peripheral nerve during development"Experimental Neurology. 174. 109-117 (2002)

Masaki T 等人：“发育过程中大鼠周围神经中肌营养不良聚糖和层粘连蛋白-α2 链的表达”实验神经学。174. 109-117 (2002)

Matsumura K et al.: "Sarcoglycan complex : a muscular supporter of dystroglycan-dystrophin interplay?"Cellular and Molecular Biology. 45. 751-762 (1999)

Matsumura K 等人：“肌聚糖复合物：肌营养不良聚糖-肌营养不良蛋白相互作用的肌肉支持者？”细胞和分子生物学。