TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia

J Neurol Neurosurg Psychiatry. 2008 Oct;79(10):1186-9. doi: 10.1136/jnnp.2007.131334.

Abstract

TAR DNA binding protein-43 (TDP-43) is found in ubiquitinated inclusions (UBIs) in some frontotemporal dementias (FTD-U). One form of FTD-U, due to mutations in the valosin containing protein (VCP) gene, occurs with an inclusion body myopathy (IBMPFD). Since IBMPFD brain has TDP-43 in UBIs, we looked for TDP-43 inclusions in IBMPFD muscle. In normal muscle, TDP-43 is present in nuclei. In IBMPFD muscle, TDP-43 is additionally present as large inclusions within UBIs in muscle cytoplasm. TDP-43 inclusions were also found in 78% of sporadic inclusion body myositis (sIBM) muscles. In IBMPFD and sIBM muscle, TDP-43 migrated with an additional band on immunoblot similar to that reported in FTD-U brains. This study adds sIBM and hereditary inclusion body myopathies to the growing list of TDP-43 positive inclusion diseases.

MeSH terms

  • Adenosine Triphosphatases / genetics
  • CD8 Antigens / immunology
  • Cell Cycle Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • Dementia* / immunology
  • Dementia* / pathology
  • Dementia* / physiopathology
  • Diagnosis, Differential
  • Electromyography
  • Humans
  • Muscle, Skeletal / immunology
  • Muscle, Skeletal / innervation
  • Muscle, Skeletal / pathology
  • Mutation, Missense / genetics
  • Myositis, Inclusion Body* / immunology
  • Myositis, Inclusion Body* / pathology
  • Myositis, Inclusion Body* / physiopathology
  • Phosphorylation
  • Point Mutation / genetics
  • Valosin Containing Protein

Substances

  • CD8 Antigens
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein