| First Author | Vogler TO | Year | 2018 |
| Journal | Nature | Volume | 563 |
| Issue | 7732 | Pages | 508-513 |
| PubMed ID | 30464263 | Mgi Jnum | J:268274 |
| Mgi Id | MGI:6260239 | Doi | 10.1038/s41586-018-0665-2 |
| Citation | Vogler TO, et al. (2018) TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle. Nature 563(7732):508-513 |
| abstractText | 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. |
