Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, USA.
Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Nature. 2018 Nov;563(7732):508-513. doi: 10.1038/s41586-018-0665-2. Epub 2018 Oct 31.
A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP-the gene that encodes TDP-43-that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here we show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.
在包括肌萎缩侧索硬化症和包涵体肌病在内的神经肌肉疾病中，一个主要的组织病理学特征是 RNA 结合蛋白 TDP-43 的细胞质聚集。虽然 TARDBP（编码 TDP-43 的基因）的罕见突变导致蛋白质错误折叠，通常会导致蛋白质聚集，但大多数患者没有 TARDBP 的任何突变。因此，大多数患者的野生型 TDP-43 聚集是通过未知机制产生的。在这里，我们表明 TDP-43 是正常骨骼肌形成所必需的蛋白质，但令人意外的是，在小鼠和人类的骨骼肌再生过程中，它会形成细胞质、类淀粉样寡聚体组装体，我们称之为肌粒体。肌粒体与编码肌节蛋白的 mRNAs 结合，并在肌纤维成熟时被清除。尽管肌粒体在正常的骨骼肌再生过程中存在，但肌粒体可以在体外引发 TDP-43 淀粉样纤维的形成，并且在包涵体肌病的小鼠模型中增加。因此，功能正常的肌粒体的组装增加或清除减少可能是细胞质 TDP-43 聚集物的来源，这些聚集物通常在神经肌肉疾病中发生。
