TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle

Thomas O. Vogler, Joshua R. Wheeler, Eric D. Nguyen, Michael P. Hughes, Kyla A. Britson, Evan Lester, Bhalchandra Rao, Nicole Dalla Betta, Oscar N. Whitney, Theodore E. Ewachiw, Edward Gomes, James Shorter, Thomas E. Lloyd, David S. Eisenberg, J. Paul Taylor, Aaron M. Johnson, Bradley B. Olwin, Roy Parker

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)508-513
Number of pages6
Issue number7732
StatePublished - Nov 22 2018

ASJC Scopus subject areas

  • General


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