TAR DNA-Binding protein 43 accumulation in protein aggregate myopathies

J Neuropathol Exp Neurol. 2009 Mar;68(3):262-73. doi: 10.1097/NEN.0b013e3181996d8f.


Protein aggregate myopathies, including myofibrillar myopathies and sporadic inclusion body myositis (sIBM), are characterized by abnormal protein aggregates composed of various muscular and ectopic proteins. Previous studies have shown the crucial role ofdysregulated transcription factors such as neuron-restrictive silencerfactor in the expression of aberrant proteins in myotilinopathies. Here, we assessed possible aberrant expression of TAR DNA-bindingprotein 43 (TDP-43), another factor involved in transcription regulation. TDP-43-immunoreactive intracytoplasmic inclusions were seen in all cases examined of myotilinopathy, desminopathy, and sIBM, and in 1 case of inclusion body myositis with Paget disease of bone and frontotemporal degeneration (IBMPFD). TAR DNA-binding protein 43 colocalized with myotilin and valosin in myotilinopathies and IBMPFD, respectively, but only occasionally colocalized with ubiquitin in myotilinopathies, desminopathies, sIBM, and IBMPFD; this indicates that accumulated TDP-43 is largely not ubiquitinated. Moreover, phosphorylated TDP-43 at Ser403/404 and Ser409/410 accumulated in the cytoplasm of vulnerable fibers but did not always colocalize with nonphosphorylated TDP-43. Cytoplasmic deposition was accompanied by decreased TDP-43 localization in the nuclei of affected fibers. These findings indicate that TDP-43 not only is another protein accumulated in myofibrillar myopathies, sIBM, and IBMPFD but also likely has a role through altered microRNA processing in the abnormal protein production, modification, and accumulation in protein aggregate myopathies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Blotting, Western
  • Connectin
  • Cytoskeletal Proteins / metabolism
  • DNA-Binding Proteins / metabolism*
  • Dementia
  • Female
  • Fluorescent Antibody Technique
  • Gene Expression
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Microscopy, Confocal
  • Middle Aged
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Myositis, Inclusion Body / metabolism*
  • Myositis, Inclusion Body / pathology
  • Peptides / metabolism
  • Phosphorylation
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ubiquitin / metabolism


  • Connectin
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • MYOT protein, human
  • Muscle Proteins
  • Peptides
  • Ubiquitin
  • valosin