1. Academic Validation
  2. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle

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

  • Nature. 2018 Nov;563(7732):508-513. doi: 10.1038/s41586-018-0665-2.
Thomas O Vogler 1 2 Joshua R Wheeler 2 3 Eric D Nguyen 2 4 Michael P Hughes 5 6 Kyla A Britson 7 8 Evan Lester 2 3 Bhalchandra Rao 3 Nicole Dalla Betta 1 Oscar N Whitney 1 Theodore E Ewachiw 1 Edward Gomes 9 James Shorter 9 Thomas E Lloyd 7 8 David S Eisenberg 5 6 10 J Paul Taylor 11 12 Aaron M Johnson 4 13 Bradley B Olwin 14 Roy Parker 15 16
Affiliations

Affiliations

  • 1 Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, USA.
  • 2 Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • 3 Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO, USA.
  • 4 Molecular Biology Program, Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • 5 Department of Biological Chemistry, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • 6 Department of Chemistry and Biochemistry, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • 7 Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 8 Departments of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 9 Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 10 Howard Hughes Medical Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
  • 11 Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 12 Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 13 University of Colorado School of Medicine RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • 14 Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, USA. olwin@colorado.edu.
  • 15 Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO, USA. roy.parker@colorado.edu.
  • 16 Howard Hughes Medical Institute, University of Colorado, Boulder, CO, USA. roy.parker@colorado.edu.
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.

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