Analysis of pathogenesis induced by defects of intermediate filament networks.

我们的超微结构和生化分析表明，plectin分子拴中间丝肌膜下致密斑块含有肌营养不良蛋白复合物。分子相互作用的进一步更精确的分析揭示，plectin结合desmuslin，这反过来，相互作用与肌营养不良相关的肌膜下的肌营养不良蛋白。除了desmuslin的互连作用，desmuslin似乎与desmin共聚，形成杂聚的中间丝。基于这些发现，我们研究了缺乏抗肌萎缩蛋白的mdx小鼠中间丝网络的表型变化。尽管肌营养不良蛋白的缺失，肌膜下仍然发现了小肌营养不良蛋白，可能是由于作为替代蛋白的urtophin的表达上调。在完整纤维的肌膜下间隙以及具有中央核的再生纤维中确定了增加的免疫反应性的网蛋白和desmuslin。mdx小鼠肌膜下的中间丝蛋白的这种积累表明desmuslin和plectin可能参与肌营养不良症的发病机制。

Our ultrastructural and biochemical analyses revealed that plectin molecules tethered intermediate filaments onto subsarcolemmal dense plaques containing dystrophin complexes. Further more precise analyses of molecular interaction disclosed that plectin bound desmuslin, which, in turn, interacted with dystrobrevin associated with dystrophins beneath the sarcolemma. In addition to interlinking role of desmuslin, desmuslin appeared to copolymerize with desmin, forming heteropolymerized intermediate filaments. Based on these findings, we studied the phenotypic changes of intermediate filament networks in mdx mice lacking dystrophin. Despite of the absence of dystrophin, dystrobrevin was still found under the sarcolemma, probably due to up regulated expression of urtophin as substitutive protein. Increased immunoreactivities of plectin and desmuslin were identified in the subsarcolemmal space of intact fibers as well as regenerating fibers with central nuclei. This accumulation of intermediate filaments proteins under the sarcolemma of mdx mice suggest desmuslin and plectin may participate in the pathogenesis of muscular dystrophy.