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Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation.

TAR DNA-binding protein 43 (TDP-43) is the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Although normal TDP-43 is a nuclear protein, pathological TDP-43 is redistributed and sequestered as insoluble aggregates in neuronal nuclei, perikarya, and neurites. Here we recapitulate these pathological phenotypes in cultured cells by altering endogenous TDP-43 nuclear trafficking and by expressing mutants with defective nuclear localization (TDP-43-DeltaNLS) or nuclear export signals (TDP-43-DeltaNES). Restricting endogenous cytoplasmic TDP-43 from entering the nucleus or preventing its exit out of the nucleus resulted in TDP-43 aggregate formation. TDP-43-DeltaNLS accumulates as insoluble cytoplasmic aggregates and sequesters endogenous TDP-43, thereby depleting normal nuclear TDP-43, whereas TDP-43-DeltaNES forms insoluble nuclear aggregates with endogenous TDP-43. Mutant forms of TDP-43 also replicate the biochemical profile of pathological TDP-43 in FTLD-U/ALS. Thus, FTLD-U/ALS pathogenesis may be linked mechanistically to deleterious perturbations of nuclear trafficking and solubility of TDP-43.

Pubmed ID: 18305110


  • Winton MJ
  • Igaz LM
  • Wong MM
  • Kwong LK
  • Trojanowski JQ
  • Lee VM


The Journal of biological chemistry

Publication Data

May 9, 2008

Associated Grants

  • Agency: NIA NIH HHS, Id: AG10124
  • Agency: NIA NIH HHS, Id: AG17586

Mesh Terms

  • Animals
  • Cell Line
  • Cell Nucleus
  • Cytoplasm
  • DNA-Binding Proteins
  • Disease
  • Gene Expression Regulation
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Nuclear Localization Signals
  • Ubiquitination