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 journalArticlepeer-review

47 Scopus citations


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
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the NIH Grant No. R01 NS095969 (PCW), McKnight Memory and Cognitive Disorders Award (PCW and LC), Robert Packard Center for ALS Research (LC and PCW) and the Amyotrophic Lateral Sclerosis Association (PCW). JPL is a recipient of a Johns Hopkins Kavli Neuroscience Discovery Institute fellowship award.

Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.


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


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