A robust TDP-43 knock-in mouse model of ALS

Shih Ling Huang, Lien Szu Wu, Min Lee, Chin Wen Chang, Wei Cheng Cheng, Yu Sheng Fang, Yun Ru Chen, Pei Lin Cheng, Che Kun James Shen

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)


Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset degenerative disorder of motor neurons. The diseased spinal cord motor neurons of more than 95% of amyotrophic lateral sclerosis (ALS) patients are characterized by the mis-metabolism of the RNA/DNA-binding protein TDP-43 (ALS-TDP), in particular, the presence of cytosolic aggregates of the protein. Most available mouse models for the basic or translational studies of ALS-TDP are based on transgenic overexpression of the TDP-43 protein. Here, we report the generation and characterization of mouse lines bearing homologous knock-in of fALS-associated mutation A315T and sALS-associated mutation N390D, respectively. Remarkably, the heterozygous TDP-43 (N390D/+) mice but not those heterozygous for the TDP-43 (A315T/+) mice develop a full spectrum of ALS-TDP-like pathologies at the molecular, cellular and behavioral levels. Comparative analysis of the mutant mice and spinal cord motor neurons (MN) derived from their embryonic stem (ES) cells demonstrates that different ALS-associated TDP-43 mutations possess critical ALS-causing capabilities and pathogenic pathways, likely modified by their genetic background and the environmental factors. Mechanistically, we identify aberrant RNA splicing of spinal cord Bcl-2 pre-mRNA and consequent increase of a negative regulator of autophagy, Bcl-2, which correlate with and are caused by a progressive increase of TDP-43, one of the early events associated with ALS-TDP pathogenesis, in the spinal cord of TDP-43 (N390D/+) mice and spinal cord MN derived from their ES cells. The TDP-43 (N390D/+) knock-in mice appear to be an ideal rodent model for basic as well as translational studies of ALS- TDP.

Original languageEnglish
Article number3
Pages (from-to)3
JournalActa neuropathologica communications
Issue number1
Publication statusPublished - Jan 21 2020


  • ALS-TDP pathogenesis
  • Amyotrophic lateral sclerosis (ALS)
  • Autonomous spinal cord motor neuron degeneration
  • Homologous knock-in mouse models with ALS-associated TDP-43 mutations
  • Mis-splicing of Bcl-2 pre-mRNA
  • TAR DNA-binding protein 43 (TDP-43)

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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