TDP-43 Skips Out on Some Exons in ALS

A new mouse model of ALS may provide insight into how changes in TDP-43 contribute to ALS. The knock-in mouse, developed by a research team led by University College London’s Pietro Fratta in England and University Hospital of the Canary Islands’ Abraham Acevedo-Arozena, exhibits key signs of ALS including muscle weakness and progressive motor neuron loss.

The Skiptics? Changes in the C-terminal low complexity domain of TDP-43 leads to the skipping of conserved constitutive exons during RNA splicing according to a new study, potentially contributing to motor neuron toxicity in the disease. [Courtesy of Fratta et al., 2018, EMBO Journal under a CC BY 4.0 license.]

The homozygous mutant mice, harboring a mutation in the C-terminal low-complexity domain of its own TDP-43, develop symptoms after one year of age. And at 2 years, about 30% of the motor neurons of these mice degenerated – at least in key regions of the lumbar spinal cord. No TDP-43 pathology, however, could be detected.

The model is one of a growing number of knock-in mice being created in hopes to more accurately recapitulate ALS to identify new targets for the disease (see November 2017, December 2017 news; Devoy et al., 2017; White et al., 2018).

The study is published on May 15 in the EMBO Journal.


Fratta P, Sivakumar P, Humphrey J, Lo K, Ricketts T, Oliveira H, Brito-Armas JM, Kalmar B, Ule A, Yu Y, Birsa N, Bodo C, Collins T, Conicella AE, Mejia Maza A, Marrero-Gagliardi A, Stewart M, Mianne J, Corrochano S, Emmett W, Codner G, Groves M, Fukumura R, Gondo Y, Lythgoe M, Pauws E, Peskett E, Stanier P, Teboul L, Hallegger M, Calvo A, Chiò A, Isaacs AM, Fawzi NL, Wang E, Housman DE, Baralle F, Greensmith L, Buratti E, Plagnol V, Fisher EM, Acevedo-Arozena A. Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis. EMBO J. 2018 May 15. pii: e98684. [PubMed].

White MA, Kim E, Duffy A, Adalbert R, Phillips BU, Peters OM, Stephenson J, Yang S, Massenzio F, Lin Z, Andrews S, Segonds-Pichon A, Metterville J, Saksida LM, Mead R, Ribchester RR, Barhomi Y, Serre T, Coleman MP, Fallon J, Bussey TJ, Brown RH Jr, Sreedharan J. TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD. Nat Neurosci. 2018 Apr;21(4):552-563. [PubMed].

Devoy A, Kalmar B, Stewart M, Park H, Burke B, Noy SJ, Redhead Y, Humphrey J, Lo K, Jaeger J, Mejia Maza A, Sivakumar P, Bertolin C, Soraru G, Plagnol V, Greensmith L, Acevedo Arozena A, Isaacs AM, Davies B, Fratta P, Fisher EMC. Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in ‘FUSDelta14’ knockin mice. Brain. 2017 Nov 1;140(11):2797-2805. [PubMed].

Further Reading

Rouaux C, Gonzalez De Aguilar JL, Dupuis L. Unmasking the skiptic task of TDP-43. EMBO J. 2018 May 16. pii: e99645. [PubMed].

disease-als RNA splicing skiptic exons tdp-43 topic-preclinical
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