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
  • 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. [email protected].
  • 15. Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO, USA. [email protected].
  • 16. Howard Hughes Medical Institute, University of Colorado, Boulder, CO, USA. [email protected].
PMID: 30464263 DOI: 10.1038/s41586-018-0665-2
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.