Desmin forms toxic, seeding-competent amyloid aggregates that persist in muscle fibers
Desmin forms toxic, seeding-competent amyloid aggregates that persist in muscle fibers
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DOI：
10.1073/pnas.1908263116
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发表时间：
2019-08-20
影响因子：
11.1
通讯作者：
Bieschke, Jan
中科院分区：
文献类型：
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作者：
Kedia, Niraja;Arhzaouy, Khalid;Bieschke, Jan
结蛋白相关性肌原纤维肌病（MFM）与神经变性相关性蛋白聚集疾病具有病理相似性。结蛋白是一种丰富的肌肉特异性中间丝，疾病突变导致其在细胞、动物和患者中聚集。我们推断，类似于神经退行性变相关蛋白，结蛋白本身可能形成淀粉样蛋白。结蛋白肽对应于假定的淀粉样蛋白生成区域形成有播种能力的淀粉样蛋白原纤维。当肽内发生疾病相关突变时，淀粉样蛋白的形成会增加，而这种转化会被抗淀粉样蛋白化合物表没食子儿茶素没食子酸酯抑制。此外，一个纯化的结蛋白片段（氨基酸117至348）含有两个淀粉样蛋白的区域形成淀粉样蛋白纤维在生理条件下。结蛋白片段衍生的淀粉样蛋白与全长结蛋白共聚集，并能够在体外将其转化为原纤维。与结蛋白单体或其他非结蛋白淀粉样蛋白相比，结蛋白淀粉样蛋白对肌管具有细胞毒性并破坏其肌原纤维组织。最后，结蛋白片段淀粉样蛋白持续引入小鼠骨骼肌。这些数据表明结蛋白形成对肌纤维有毒的种子活性淀粉样蛋白。此外，已知干扰淀粉样蛋白形成和繁殖的小分子可能在MFM中具有治疗潜力。
Desmin-associated myofibrillar myopathy (MFM) has pathologic similarities to neurodegeneration-associated protein aggregate diseases. Desmin is an abundant muscle-specific intermediate filament, and disease mutations lead to its aggregation in cells, animals, and patients. We reasoned that similar to neurodegeneration-associated proteins, desmin itself may form amyloid. Desmin peptides corresponding to putative amyloidogenic regions formed seeding-competent amyloid fibrils. Amyloid formation was increased when disease-associated mutations were made within the peptide, and this conversion was inhibited by the anti-amyloid compound epigallocatechin-gallate. Moreover, a purified desmin fragment (aa 117 to 348) containing both amyloidogenic regions formed amyloid fibrils under physiologic conditions. Desmin fragment-derived amyloid coaggregated with full-length desmin and was able to template its conversion into fibrils in vitro. Desmin amyloids were cytotoxic to myotubes and disrupted their myofibril organization compared with desmin monomer or other nondesmin amyloids. Finally, desmin fragment amyloid persisted when introduced into mouse skeletal muscle. These data suggest that desmin forms seeding-competent amyloid that is toxic to myofibers. Moreover, small molecules known to interfere with amyloid formation and propagation may have therapeutic potential in MFM.