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Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice.

BACKGROUND: Abnormal distribution, modification and aggregation of transactivation response DNA-binding protein 43 (TDP-43) are the hallmarks of multiple neurodegenerative diseases, especially frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Researchers have identified 44 mutations in the TARDBP gene that encode TDP-43 as causative for cases of sporadic and familial ALS http://www.molgen.ua.ac.be/FTDMutations/. Certain mutant forms of TDP-43, such as M337V, are associated with increased low molecular weight (LMW) fragments compared to wild-type (WT) TDP-43 and cause neuronal apoptosis and developmental delay in chick embryos. Such findings support a direct link between altered TDP-43 function and neurodegeneration. RESULTS: To explore the pathogenic properties of the M337V mutation, we generated and characterized two mouse lines expressing human TDP-43 (hTDP-43(M337V)) carrying this mutation. hTDP-43(M337V) was expressed primarily in the nuclei of neurons in the brain and spinal cord, and intranuclear and cytoplasmic phosphorylated TDP-43 aggregates were frequently detected. The levels of TDP-43 LMW products of ~25 kDa and ~35 kDa species were also increased in the transgenic mice. Moreover, overexpression of hTDP-43(M337V) dramatically down regulated the levels of mouse TDP-43 (mTDP-43) protein and RNA, indicating TDP-43 levels are tightly controlled in mammalian systems. TDP-43M337V mice displayed reactive gliosis, widespread ubiquitination, chromatolysis, gait abnormalities, and early lethality. Abnormal cytoplasmic mitochondrial aggregates and abnormal phosphorylated tau were also detected in the mice. CONCLUSION: Our novel TDP-43M337V mouse model indicates that overexpression of hTDP-43(M337V) alone is toxic in vivo. Because overexpression of hTDP-43 in wild-type TDP-43 and TDP-43M337V mouse models produces similar phenotypes, the mechanisms causing pathogenesis in the mutant model remain unknown. However, our results suggest that overexpression of the hTDP-43(M337V) can cause neuronal dysfunction due to its effect on a number of cell organelles and proteins, such as mitochondria and TDP-43, that are critical for neuronal activity. The mutant model will serve as a valuable tool in the development of future studies designed to uncover pathways associated with TDP-43 neurotoxicity and the precise roles TDP-43 RNA targets play in neurodegeneration.

Pubmed ID: 22029574


  • Xu YF
  • Zhang YJ
  • Lin WL
  • Cao X
  • Stetler C
  • Dickson DW
  • Lewis J
  • Petrucelli L


Molecular neurodegeneration

Publication Data

November 17, 2011

Associated Grants

  • Agency: NINDS NIH HHS, Id: 1R21NS071097-01
  • Agency: NIA NIH HHS, Id: 5R01AG026251-04
  • Agency: NIA NIH HHS, Id: P01 AG003949
  • Agency: NIA NIH HHS, Id: P01-AG17216-08
  • Agency: NINDS NIH HHS, Id: R01 NS 063964-01

Mesh Terms

  • Animals
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Transgenic
  • Mitochondria
  • Movement Disorders
  • Mutation
  • Nerve Degeneration
  • Neurodegenerative Diseases
  • Neurons
  • Spinal Cord
  • tau Proteins