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 () and Roy Parker ()
Additional contact information
Thomas O. Vogler: University of Colorado
Joshua R. Wheeler: University of Colorado Anschutz Medical Campus
Eric D. Nguyen: University of Colorado Anschutz Medical Campus
Michael P. Hughes: University of California, Los Angeles (UCLA)
Kyla A. Britson: Johns Hopkins University School of Medicine
Evan Lester: University of Colorado Anschutz Medical Campus
Bhalchandra Rao: University of Colorado
Nicole Dalla Betta: University of Colorado
Oscar N. Whitney: University of Colorado
Theodore E. Ewachiw: University of Colorado
Edward Gomes: Perelman School of Medicine, University of Pennsylvania
James Shorter: Perelman School of Medicine, University of Pennsylvania
Thomas E. Lloyd: Johns Hopkins University School of Medicine
David S. Eisenberg: University of California, Los Angeles (UCLA)
J. Paul Taylor: St. Jude Children’s Research Hospital
Aaron M. Johnson: University of Colorado Anschutz Medical Campus
Bradley B. Olwin: University of Colorado
Roy Parker: University of Colorado

Nature, 2018, vol. 563, issue 7732, 508-513

Abstract: Abstract 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.

Keywords: Myofibres; Inclusion Body Myopathy; Skeletal Muscle Formation; Proximity Ligation Assay; Muscle Stem Cells (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0665-2

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