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

Authors :
David E. Housman
Prasanth Sivakumar
Martina Hallegger
Cristian Bodo
Bernadett Kalmar
Warren Emmett
Hugo Alexandre Mendes Oliveira
Philip Stanier
Adrian M. Isaacs
Alexander E. Conicella
Linda Greensmith
Lydia Teboul
Pietro Fratta
Alessandro Marrero-Gagliardi
Vincent Plagnol
Nicolas L. Fawzi
José M. Brito-Armas
Nicol Birsa
Yichao Yu
Erwin Pauws
Emma Peskett
Joffrey Mianné
Agnieszka M. Ule
Gemma F. Codner
T. Ricketts
Andrea Calvo
Silvia Corrochano
Toby Collins
Jack Humphrey
M Groves
Mark F. Lythgoe
Emanuele Buratti
Francisco E. Baralle
Eric T. Wang
Adriano Chiò
Alan Mejia Maza
Michelle Stewart
Yoichi Gondo
Ryutaro Fukumura
Kitty Lo
Elizabeth M. C. Fisher
Abraham Acevedo-Arozena
Massachusetts Institute of Technology. Department of Biology
Wang, Eric T
Housman, David E
Source :
The EMBO Journal, EMBRO Press
Publication Year :
2018
Publisher :
EMBO, 2018.

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 &quot;skiptic&quot; 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. Keywords: ALS; cryptic exon; skiptic exon; splicing; TDP-43

Details

ISSN :
14602075 and 02614189
Volume :
37
Database :
OpenAIRE
Journal :
The EMBO Journal
Accession number :
edsair.doi.dedup.....9d557cc26637b8b4264f70b21760dc09
Full Text :
https://doi.org/10.15252/embj.201798684