Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

• Pietro Fratta ^[6] ; Prasanth Sivakumar ^[6] ; Jack Humphrey ^[7] ; Kitty Lo ^[8] ; Thomas Ricketts ^[9] ; Hugo Oliveira ^[9] ; Jose M Brito‐Armas ^[1] ; Bernadett Kalmar ^[6] ; Agnieszka Ule ^[6] ; Yichao Yu ^[2] ; Nicol Birsa ^[6] ; Cristian Bodo ^[6] ; Toby Collins ^[6] ; Alexander E Conicella ^[3] ; Alan Mejia Maza ^[6] ; Alessandro Marrero‐Gagliardi ^[1] ; Michelle Stewart ^[10] ; Joffrey Mianne ^[10] ; Silvia Corrochano ^[9] ; Warren Emmett ^[8] ; Gemma Codner ^[10] ; Michael Groves ^[6] ; Ryutaro Fukumura ^[11] ; Yoichi Gondo ^[11] ; Mark Lythgoe ^[2] ; Erwin Pauws ^[12] ; Emma Peskett ^[12] ; Philip Stanier ^[12] ; Lydia Teboul ^[10] ; Martina Hallegger ^[13] ; Andrea Calvo ^[4] ; Adriano Chiò ^[4] ; Adrian M Isaacs ^[14] ; Nicolas L Fawzi ^[3] ; Eric Wang ^[5] ; David E Housman ^[5] ; Francisco Baralle ^[15] ; Linda Greensmith ^[6] ; Emanuele Buratti ^[15] ; Vincent Plagnol ^[8] ; Elizabeth MC Fisher ^[6] ; Abraham Acevedo‐Arozena ^[1]
  1. [1] Hospital Universitario de Canarias

     Hospital Universitario de Canarias

     San Cristóbal de La Laguna, España

     
  2. [2] University College London

     University College London

     Reino Unido

     
  3. [3] Brown University

     Brown University

     City of Providence, Estados Unidos

     
  4. [4] University of Turin

     University of Turin

     Torino, Italia

     
  5. [5] Massachusetts Institute of Technology

     Massachusetts Institute of Technology

     City of Cambridge, Estados Unidos

     
  6. [6] 1 UCL Institute of Neurology, and MRC Centre for Neuromuscular Disease London UK
  7. [7] 1 UCL Institute of Neurology, and MRC Centre for Neuromuscular Disease London UK; 2 UCL Genetics Institute London UK
  8. [8] 2 UCL Genetics Institute London UK
  9. [9] 3 MRC Mammalian Genetics Unit Harwell UK
  10. [10] 7 MRC Mary Lyon Centre Harwell UK
  11. [11] 8 Mutagenesis and Genomics Team RIKEN BioResource Center Tsukuba Ibaraki Japan
  12. [12] 9 UCL Institute of Child Health London UK
  13. [13] 10 UCL Institute of Neurology and Francis Crick Institute London UK
  14. [14] 1 UCL Institute of Neurology, and MRC Centre for Neuromuscular Disease London UK; 12 UK Dementia Research Institute at UCL UCL Institute of Neurology London UK
  15. [15] 15 International Center for Genomic Engineering and Biotechnology (ICGEB) Trieste Italy

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 11, 2018, págs. 6-6
• Idioma: inglés
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• Resumen

  • TDP‐43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP‐43 function at physiological levels both in vitro and in vivo. Interestingly, we find that mutations within the C‐terminal domain of TDP‐43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP‐43 loss‐ and gain‐of‐function effects. TDP‐43 gain‐of‐function effects in these mice reveal a novel category of splicing events controlled by TDP‐43, referred to as “skiptic” exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain‐of‐function mutation in endogenous Tardbp causes an adult‐onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain‐of‐function and skiptic exons in ALS patient‐derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP‐43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages.