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 Lucian Chen, Philip Chun Wong

Research output: Contribution to journalArticle

Abstract

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)
JournalActa neuropathologica
DOIs
StatePublished - Jan 1 2019

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Motor Neurons
Amyotrophic Lateral Sclerosis
RNA-Binding Proteins
Transcriptome
Drosophila
Axons
RNA
Proteins

Keywords

  • 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

Cite this

Splicing repression is a major function of TDP-43 in motor neurons. / Donde, Aneesh; Sun, Mingkuan; Ling, Jonathan P.; Braunstein, Kerstin E.; Pang, Bo; Wen, Xinrui; Cheng, Xueying; Chen, Liam Lucian; Wong, Philip Chun.

In: Acta neuropathologica, 01.01.2019.

Research output: Contribution to journalArticle

Donde, Aneesh ; Sun, Mingkuan ; Ling, Jonathan P. ; Braunstein, Kerstin E. ; Pang, Bo ; Wen, Xinrui ; Cheng, Xueying ; Chen, Liam Lucian ; Wong, Philip Chun. / Splicing repression is a major function of TDP-43 in motor neurons. In: Acta neuropathologica. 2019.
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