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

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 funct...

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Autores principales: Fratta, Pietro, Sivakumar, Prasanth, Humphrey, Jack, Lo, Kitty, Ricketts, Thomas, Oliveira, Hugo, Brito‐Armas, Jose M, Kalmar, Bernadett, Ule, Agnieszka, Yu, Yichao, Birsa, Nicol, Bodo, Cristian, Collins, Toby, Conicella, Alexander E, Mejia Maza, Alan, Marrero‐Gagliardi, 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, Acevedo‐Arozena, Abraham
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983119/
https://www.ncbi.nlm.nih.gov/pubmed/29764981
http://dx.doi.org/10.15252/embj.201798684
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author Fratta, Pietro
Sivakumar, Prasanth
Humphrey, Jack
Lo, Kitty
Ricketts, Thomas
Oliveira, Hugo
Brito‐Armas, Jose M
Kalmar, Bernadett
Ule, Agnieszka
Yu, Yichao
Birsa, Nicol
Bodo, Cristian
Collins, Toby
Conicella, Alexander E
Mejia Maza, Alan
Marrero‐Gagliardi, 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
Acevedo‐Arozena, Abraham
author_facet Fratta, Pietro
Sivakumar, Prasanth
Humphrey, Jack
Lo, Kitty
Ricketts, Thomas
Oliveira, Hugo
Brito‐Armas, Jose M
Kalmar, Bernadett
Ule, Agnieszka
Yu, Yichao
Birsa, Nicol
Bodo, Cristian
Collins, Toby
Conicella, Alexander E
Mejia Maza, Alan
Marrero‐Gagliardi, 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
Acevedo‐Arozena, Abraham
author_sort Fratta, Pietro
collection PubMed
description 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.
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spelling pubmed-59831192018-06-07 Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis Fratta, Pietro Sivakumar, Prasanth Humphrey, Jack Lo, Kitty Ricketts, Thomas Oliveira, Hugo Brito‐Armas, Jose M Kalmar, Bernadett Ule, Agnieszka Yu, Yichao Birsa, Nicol Bodo, Cristian Collins, Toby Conicella, Alexander E Mejia Maza, Alan Marrero‐Gagliardi, 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 Acevedo‐Arozena, Abraham EMBO J Articles 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. John Wiley and Sons Inc. 2018-05-15 2018-06-01 /pmc/articles/PMC5983119/ /pubmed/29764981 http://dx.doi.org/10.15252/embj.201798684 Text en © 2018 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Fratta, Pietro
Sivakumar, Prasanth
Humphrey, Jack
Lo, Kitty
Ricketts, Thomas
Oliveira, Hugo
Brito‐Armas, Jose M
Kalmar, Bernadett
Ule, Agnieszka
Yu, Yichao
Birsa, Nicol
Bodo, Cristian
Collins, Toby
Conicella, Alexander E
Mejia Maza, Alan
Marrero‐Gagliardi, 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
Acevedo‐Arozena, Abraham
Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis
title Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis
title_full Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis
title_fullStr Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis
title_full_unstemmed Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis
title_short Mice with endogenous TDP‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis
title_sort mice with endogenous tdp‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983119/
https://www.ncbi.nlm.nih.gov/pubmed/29764981
http://dx.doi.org/10.15252/embj.201798684
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