ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43

Eveline S. Arnold, Shuo-Chien Ling, Stephanie C. Huelga, Clotilde Lagier-Tourenne, Magdalini Polymenidou, Dara Ditsworth, Holly B. Kordasiewicz, Melissa McAlonis-Downes, Oleksandr Platoshyn, Philippe A. Parone, Sandrine Da Cruz, Kevin M. Clutario, Debbie Swing, Lino Tessarollo, Martin Marsala, Christopher E. Shaw, Gene W. Yeo, Don W. Cleveland*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

326 Citations (Scopus)

Abstract

Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43(Q331K) and TDP-43(M337V)), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell type-selective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43-dependent alternative splicing events conferred by both human wild-type and mutant TDP-43(Q331K), but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43(Q331K) enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage.

Original languageEnglish
Article numberN/A
Pages (from-to)E736-E745
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number8
DOIs
Publication statusPublished - 19 Feb 2013

Keywords

  • neurodegeneration
  • RNA binding proteins
  • frontotemporal dementia
  • AMYOTROPHIC-LATERAL-SCLEROSIS
  • FRONTOTEMPORAL LOBAR DEGENERATION
  • DNA-BINDING PROTEIN-43
  • TRANSGENIC MICE
  • SPINAL-CORD
  • PROCESSING PROTEIN
  • CELLULAR TOXICITY
  • TARDBP MUTATIONS
  • ALPHA-SYNUCLEIN
  • MUTANT TDP-43

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