Splicing repression is a major function of TDP-43 in motor neurons

Aneesh Donde, Mingkuan Sun, Jonathan P. Ling, Kerstin E. Braunstein, Bo Pang, Xinrui Wen, Xueying Cheng, Liam Chen, Philip C. Wong

Research output: Contribution to journalArticle


Nuclear depletion of TDP-43, an essential RNA binding protein, may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). As several functions have been ascribed to this protein, the critical role(s) of TDP-43 in motor neurons that may be compromised in ALS remains unknown. We show here that TDP-43 mediated splicing repression, which serves to protect the transcriptome by preventing aberrant splicing, is central to the physiology of motor neurons. Expression in Drosophila TDP-43 knockout models of a chimeric repressor, comprised of the RNA recognition domain of TDP-43 fused to an unrelated splicing repressor, RAVER1, attenuated motor deficits and extended lifespan. Likewise, AAV9-mediated delivery of this chimeric rescue repressor to mice lacking TDP-43 in motor neurons delayed the onset, slowed the progression of motor symptoms, and markedly extended their lifespan. In treated mice lacking TDP-43 in motor neurons, aberrant splicing was significantly decreased and accompanied by amelioration of axon degeneration and motor neuron loss. This AAV9 strategy allowed long-term expression of the chimeric repressor without any adverse effects. Our findings establish that splicing repression is a major function of TDP-43 in motor neurons and strongly support the idea that loss of TDP-43-mediated splicing fidelity represents a key pathogenic mechanism underlying motor neuron loss in ALS.

Original languageEnglish (US)
Pages (from-to)813-826
Number of pages14
JournalActa neuropathologica
Issue number5
StatePublished - Nov 1 2019


  • Amyotrophic lateral sclerosis
  • Cryptic exon
  • Drosophila
  • Motor neuron
  • Mouse
  • TDP-43

ASJC Scopus subject areas

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

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    Donde, A., Sun, M., Ling, J. P., Braunstein, K. E., Pang, B., Wen, X., Cheng, X., Chen, L., & Wong, P. C. (2019). Splicing repression is a major function of TDP-43 in motor neurons. Acta neuropathologica, 138(5), 813-826. https://doi.org/10.1007/s00401-019-02042-8