Format

Send to

Choose Destination
Nature. 2018 Nov;563(7732):508-513. doi: 10.1038/s41586-018-0665-2. Epub 2018 Oct 31.

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

Author information

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.

PMID:
30464263
PMCID:
PMC6324568
[Available on 2019-04-30]
DOI:
10.1038/s41586-018-0665-2

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center