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Mice with endogenous TDP ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis
Author(s) -
Fratta Pietro,
Sivakumar Prasanth,
Humphrey Jack,
Lo Kitty,
Ricketts Thomas,
Oliveira Hugo,
BritoArmas Jose M,
Kalmar Bernadett,
Ule Agnieszka,
Yu Yichao,
Birsa Nicol,
Bodo Cristian,
Collins Toby,
Conicella Alexander E,
Mejia Maza Alan,
MarreroGagliardi Alessandro,
Stewart Michelle,
Mianne Joffrey,
Corrochano Silvia,
Emmett Warren,
Codner Gemma,
Groves Michael,
Fukumura Ryutaro,
Gondo Yoichi,
Lythgoe Mark,
Pauws Erwin,
Peskett Emma,
Stanier Philip,
Teboul Lydia,
Hallegger Martina,
Calvo Andrea,
Chiò Adriano,
Isaacs Adrian M,
Fawzi Nicolas L,
Wang Eric,
Housman David E,
Baralle Francisco,
Greensmith Linda,
Buratti Emanuele,
Plagnol Vincent,
Fisher Elizabeth MC,
AcevedoArozena Abraham
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201798684
Subject(s) - amyotrophic lateral sclerosis , biology , rna splicing , endogeny , gain of function , mutation , genetics , function (biology) , alternative splicing , microbiology and biotechnology , gene , messenger rna , biochemistry , rna , medicine , disease
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.