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

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.

Pubmed ID: 23382207


  • Arnold ES
  • Ling SC
  • Huelga SC
  • Lagier-Tourenne C
  • Polymenidou M
  • Ditsworth D
  • Kordasiewicz HB
  • McAlonis-Downes M
  • Platoshyn O
  • Parone PA
  • Da Cruz S
  • Clutario KM
  • Swing D
  • Tessarollo L
  • Marsala M
  • Shaw CE
  • Yeo GW
  • Cleveland DW


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 19, 2013

Associated Grants

  • Agency: Wellcome Trust, Id: 089701
  • Agency: Medical Research Council, Id: G0300329
  • Agency: NHGRI NIH HHS, Id: HG004659
  • Agency: Medical Research Council, Id: MC_G1000733
  • Agency: NINDS NIH HHS, Id: NS069144
  • Agency: NINDS NIH HHS, Id: NS075216
  • Agency: NINDS NIH HHS, Id: NS075449
  • Agency: NHGRI NIH HHS, Id: R01 HG004659
  • Agency: NINDS NIH HHS, Id: R01 NS075449
  • Agency: NIA NIH HHS, Id: T32 AG 000216
  • Agency: NIGMS NIH HHS, Id: T32 GM008666
  • Agency: NIGMS NIH HHS, Id: T32 GM008666
  • Agency: Wellcome Trust, Id:

Mesh Terms

  • Amyotrophic Lateral Sclerosis
  • Animals
  • Cell Nucleus
  • DNA-Binding Proteins
  • Mice
  • Mice, Transgenic
  • Mutation
  • RNA Splicing
  • Real-Time Polymerase Chain Reaction
  • Ubiquitination