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

Journal article

P. Fratta, P. Sivakumar, J. Humphrey, K. Lo, T. Ricketts, H. Oliveira, J. M. Brito-Armas, B. Kalmar, A. Ule, Yichao Yu, N. Birsa, C. Bodo, T. Collins, Alexander E. Conicella, Alan Mejia Maza, A. Marrero-Gagliardi, M. Stewart, J. Mianné, Silvia Corrochano, W. Emmett, G. Codner, M. Groves, R. Fukumura, Y. Gondo, M. Lythgoe, E. Pauws, E. Peskett, P. Stanier, L. Teboul, Martina Hallegger, A. Calvo, A. Chiò, A. Isaacs, N. Fawzi, Eric T. Wang, D. Housman, F. Baralle, L. Greensmith, E. Buratti, V. Plagnol, E. Fisher, A. Acevedo-Arozena
EMBO Journal, 2018

Semantic Scholar DOI PubMedCentral PubMed

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APA Click to copy
Fratta, P., Sivakumar, P., Humphrey, J., Lo, K., Ricketts, T., Oliveira, H., … Acevedo-Arozena, A. (2018). Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis. EMBO Journal.

Chicago/Turabian Click to copy
Fratta, P., P. Sivakumar, J. Humphrey, K. Lo, T. Ricketts, H. Oliveira, J. M. Brito-Armas, et al. “Mice with Endogenous TDP‐43 Mutations Exhibit Gain of Splicing Function and Characteristics of Amyotrophic Lateral Sclerosis.” EMBO Journal (2018).

MLA Click to copy
Fratta, P., et al. “Mice with Endogenous TDP‐43 Mutations Exhibit Gain of Splicing Function and Characteristics of Amyotrophic Lateral Sclerosis.” EMBO Journal, 2018.

BibTeX Click to copy

@article{p2018a,
  title = {Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis},
  year = {2018},
  journal = {EMBO Journal},
  author = {Fratta, P. and Sivakumar, P. and Humphrey, J. and Lo, K. and Ricketts, T. and Oliveira, H. and Brito-Armas, J. M. and Kalmar, B. and Ule, A. and Yu, Yichao and Birsa, N. and Bodo, C. and Collins, T. and Conicella, Alexander E. and Maza, Alan Mejia and Marrero-Gagliardi, A. and Stewart, M. and Mianné, J. and Corrochano, Silvia and Emmett, W. and Codner, G. and Groves, M. and Fukumura, R. and Gondo, Y. and Lythgoe, M. and Pauws, E. and Peskett, E. and Stanier, P. and Teboul, L. and Hallegger, Martina and Calvo, A. and Chiò, A. and Isaacs, A. and Fawzi, N. and Wang, Eric T. and Housman, D. and Baralle, F. and Greensmith, L. and Buratti, E. and Plagnol, V. and Fisher, E. and Acevedo-Arozena, A.}
}

Abstract

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.