National Center of Neuroscience, NCNP, Kodairashi, Tokyo 187-8502, Japan.
Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(8):798-821. doi: 10.2183/pjab.86.798.
In 1987, about 150 years after the discovery of Duchenne muscular dystrophy (DMD), its responsible gene, the dystrophin gene, was cloned by Kunkel. This was a new substance. During these 20 odd years after the cloning, our understanding on dystrophin as a component of the subsarcolemmal cytoskeleton networks and on the pathomechanisms of and experimental therapeutics for DMD has been greatly enhanced. During this paradigm change, I was fortunately able to work as an active researcher on its frontiers for 12 years. After we discovered that dystrophin is located on the cell membrane in 1988, we studied the architecture of dystrophin and dystrophin-associated proteins (DAPs) complex in order to investigate the function of dystrophin and pathomechanism of DMD. During the conduct of these studies, we came to consider that the dystrophin-DAP complex serves to transmembranously connect the subsarcolemmal cytoskeleton networks and basal lamina to protect the lipid bilayer. It then became our working hypothesis that injury of the lipid bilayer upon muscle contraction is the cause of DMD. During this process, we predicted that subunits of the sarcoglycan (SG) complex are responsible for respective types of DMD-like muscular dystrophy with autosomal recessive inheritance. Our prediction was confirmed to be true by many researchers including ourselves. In this review, I will try to explain what we observed and how we considered concerning the architecture and function of the dystrophin-DAP complex, and the pathomechanisms of DMD and related muscular dystrophies.
1987 年，在发现杜氏肌营养不良症（DMD）大约 150 年后，其致病基因——肌营养不良蛋白基因，被 Kunkel 克隆。这是一种新物质。在克隆后的 20 多年里，我们对肌营养不良蛋白作为肌小节下细胞骨架网络的组成部分，以及 DMD 的病理机制和实验治疗的理解得到了极大的提高。在这一范式转变中，我有幸作为一名积极的研究人员，在其前沿领域工作了 12 年。1988 年我们发现肌营养不良蛋白位于细胞膜上后，我们研究了肌营养不良蛋白和肌营养不良蛋白相关蛋白（DAPs）复合物的结构，以研究肌营养不良蛋白的功能和 DMD 的病理机制。在进行这些研究的过程中，我们开始认为肌营养不良蛋白-DAP 复合物的作用是将肌小节下细胞骨架网络和基底膜通过跨膜连接起来，以保护脂质双层。因此，我们的工作假说认为，肌肉收缩时脂质双层的损伤是 DMD 的原因。在此过程中，我们预测，突触糖蛋白（SG）复合物的亚基负责各自类型的常染色体隐性遗传的 DMD 样肌营养不良症。我们的预测被包括我们在内的许多研究人员证实是正确的。在这篇综述中，我将尝试解释我们观察到的现象，以及我们如何考虑肌营养不良蛋白-DAP 复合物的结构和功能，以及 DMD 和相关肌营养不良症的病理机制。
