Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis

Chunxing Yang, Hongyan Wang, Tao Qiao, Bin Yang, Leonardo Aliaga, Linghua Qiu, Weijia Tan, Johnny Salameh, Diane M. McKenna-Yasek, Thomas Smith, Lingtao Peng, Melissa J. Moore, Robert H. Brown, Huaibin Cai, Zuoshang Xu

Research output: Contribution to journalArticlepeer-review


Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease that causes motor neuron degeneration, progressive motor dysfunction, paralysis, and death. Although multiple causes have been identified for this disease, >95% of ALS cases show aggregation of transactive response DNA binding protein (TDP-43) accompanied by its nuclear depletion. Therefore, the TDP-43 pathology may be a converging point in the pathogenesis that originates from various initial triggers. The aggregation is thought to result from TDP-43 misfolding, which could generate cellular toxicity. However, the aggregation as well as the nuclear depletion could also lead to a partial loss of TDP-43 function or TDP-43 dysfunction. To investigate the impact of TDP-43 dysfunction, we generated a transgenic mouse model for a partial loss of TDP-43 function using transgenic RNAi. These mice show ubiquitous transgene expression and TDP-43 knockdown in both the periphery and the central nervous system (CNS). Strikingly, these mice develop progressive neurodegeneration prominently in cortical layer V and spinal ventral horn, motor dysfunction, paralysis, and death. Furthermore, examination of splicing patterns of TDP-43 target genes in human ALS revealed changes consistent with TDP-43 dysfunction. These results suggest that the CNS, particularly motor neurons, possess a heightened vulnerability to TDP-43 dysfunction. Additionally, because TDP-43 knockdown predominantly occur in astrocytes in the spinal cord of these mice, our results suggest that TDP-43 dysfunction in astrocytes is an important driver for motor neuron degeneration and clinical phenotypes of ALS.

Original languageEnglish (US)
Pages (from-to)E1121-E1129
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number12
StatePublished - Mar 25 2014
Externally publishedYes


  • FTD
  • FTLD
  • Lou Gehrig's disease
  • Neurodegenerative disease
  • Noncell autonomous toxicity

ASJC Scopus subject areas

  • General


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