Chemical chaperone ameliorates pathological protein aggregation in plectin-deficient muscle
Chemical chaperone ameliorates pathological protein aggregation in plectin-deficient muscle
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DOI：
10.1172/jci71919
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发表时间：
2014-03-01
影响因子：
15.9
通讯作者：
Wiche, Gerhard
中科院分区：
文献类型：
--
作者：
Winter, Lilli;Staszewska, Ilona;Wiche, Gerhard
广泛表达的多功能细胞连接蛋白plectin对肌纤维的完整性和细胞结构是必不可少的。伴有肌营养不良的单纯性大疱性表皮松解症(EBS-MD)患者和骨骼肌中缺乏凝集素的小鼠表现出病理性的结蛋白阳性蛋白聚集和Z盘错位，这是肌纤维肌病(MFMs)的特征。在这里，我们建立了永生化的小鼠成肌细胞系，以在分子和单细胞水平上研究肌萎缩侧索硬化症的发病机制。来源于成肌细胞的Plectin缺陷肌管功能齐全，反映了EBS-MD肌纤维的病理特征，包括结蛋白阳性蛋白聚集体的存在和肌原纤维装置的同时紊乱。使用这个细胞模型，我们证明了凝集素缺乏导致中间细丝网络和肌节动力学增加，显著上调HSPs，并降低机械拉伸后肌管的弹性。目前，还没有特定的治疗方法或治疗方法可用于改善与Plectin相关的或其他形式的MFMs；因此，我们评估了化学伴侣缓解Plectin病的治疗潜力。经4-苯丁酸酯处理后，肌管和肌管缺陷小鼠的病理表型均有明显改善。总之，这些数据证明了MFM细胞模型的生物学相关性，并表明该模型具有开发EBS-MD治疗方法的潜在用途。
The ubiquitously expressed multifunctional cytolinker protein plectin is essential for muscle fiber integrity and myofiber cytoarchitecture. Patients suffering from plectinopathy-associated epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and mice lacking plectin in skeletal muscle display pathological desmin-positive protein aggregation and misalignment of Z-disks, which are hallmarks of myofibrillar myopathies (MFMs). Here, we developed immortalized murine myoblast cell lines to examine the pathogenesis of plectinopathies at the molecular and single cell level. Plectin-deficient myotubes, derived from myoblasts, were fully functional and mirrored the pathological features of EBS-MD myofibers, including the presence of desmin-positive protein aggregates and a concurrent disarrangement of the myofibrillar apparatus. Using this cell model, we demonstrated that plectin deficiency leads to increased intermediate filament network and sarcomere dynamics, marked upregulation of HSPs, and reduced myotube resilience following mechanical stretch. Currently, no specific therapy or treatment is available to improve plectin-related or other forms of MFMs; therefore, we assessed the therapeutic potential of chemical chaperones to relieve plectinopathies. Treatment with 4-phenylbutyrate resulted in remarkable amelioration of the pathological phenotypes in plectin-deficient myotubes as well as in plectin-deficient mice. Together, these data demonstrate the biological relevance of the MFM cell model and suggest that this model has potential use for the development of therapeutic approaches for EBS-MD.