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Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice.

Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions. We have generated transgenic (TDP-43PrP) mice expressing full-length human TDP-43 (hTDP-43) driven by the mouse prion promoter to provide a tool to analyze the role of wild-type hTDP-43 in the brain and spinal cord. Expression of hTDP-43 caused a dose-dependent downregulation of mouse TDP-43 RNA and protein. Moderate overexpression of hTDP-43 resulted in TDP-43 truncation, increased cytoplasmic and nuclear ubiquitin levels, and intranuclear and cytoplasmic aggregates that were immunopositive for phosphorylated TDP-43. Of note, abnormal juxtanuclear aggregates of mitochondria were observed, accompanied by enhanced levels of Fis1 and phosphorylated DLP1, key components of the mitochondrial fission machinery. Conversely, a marked reduction in mitofusin 1 expression, which plays an essential role in mitochondrial fusion, was observed in TDP-43PrP mice. Finally, TDP-43PrP mice showed reactive gliosis, axonal and myelin degeneration, gait abnormalities, and early lethality. This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity.

Pubmed ID: 20702714


  • Xu YF
  • Gendron TF
  • Zhang YJ
  • Lin WL
  • D'Alton S
  • Sheng H
  • Casey MC
  • Tong J
  • Knight J
  • Yu X
  • Rademakers R
  • Boylan K
  • Hutton M
  • McGowan E
  • Dickson DW
  • Lewis J
  • Petrucelli L


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

August 11, 2010

Associated Grants

  • Agency: NIA NIH HHS, Id: 2R56AG026251- 03A1
  • Agency: NIA NIH HHS, Id: P01 AG017216
  • Agency: NIA NIH HHS, Id: P01 AG017216-089001
  • Agency: NIA NIH HHS, Id: P01-AG17216-08
  • Agency: NIA NIH HHS, Id: P50 AG016574
  • Agency: NIA NIH HHS, Id: P50 AG016574-12
  • Agency: NIA NIH HHS, Id: P50 AG016574-126177
  • Agency: NIA NIH HHS, Id: P50 AG016574-126180
  • Agency: NIA NIH HHS, Id: P50AG16574
  • Agency: NIA NIH HHS, Id: R01 AG026251
  • Agency: NIA NIH HHS, Id: R01 AG026251-04
  • Agency: NINDS NIH HHS, Id: R01 NS 063964-01
  • Agency: NIA NIH HHS, Id: R01AG026251
  • Agency: NIA NIH HHS, Id: R56 AG026251
  • Agency: NIA NIH HHS, Id: R56 AG026251-03A1

Mesh Terms

  • Analysis of Variance
  • Animals
  • Body Weight
  • Brain
  • DNA-Binding Proteins
  • GTP Phosphohydrolases
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Microtubule-Associated Proteins
  • Mitochondria
  • Mitochondrial Proteins
  • Motor Neurons
  • Movement Disorders
  • Mutation
  • Nerve Degeneration
  • Phosphorylation
  • Prions
  • Silver Staining
  • Spinal Cord