10779/crick.12652712.v1
Pietro Fratta
Pietro
Fratta
Prasanth Sivakumar
Prasanth
Sivakumar
Jack Humphrey
Jack
Humphrey
Kitty Lo
Kitty
Lo
Thomas Ricketts
Thomas
Ricketts
Hugo Oliveira
Hugo
Oliveira
Jose M Brito-Armas
Jose M
Brito-Armas
Bernadett Kalmar
Bernadett
Kalmar
Agnieszka Ule
Agnieszka
Ule
Yichao Yu
Yichao
Yu
Nicol Birsa
Nicol
Birsa
Cristian Bodo
Cristian
Bodo
Toby Collins
Toby
Collins
Alexander E Conicella
Alexander E
Conicella
Alan Mejia Maza
Alan Mejia
Maza
Alessandro Marrero-Gagliardi
Alessandro
Marrero-Gagliardi
Michelle Stewart
Michelle
Stewart
Joffrey Mianne
Joffrey
Mianne
Silvia Corrochano
Silvia
Corrochano
Warren Emmett
Warren
Emmett
Gemma Codner
Gemma
Codner
Michael Groves
Michael
Groves
Ryutaro Fukumura
Ryutaro
Fukumura
Yoichi Gondo
Yoichi
Gondo
Mark Lythgoe
Mark
Lythgoe
Erwin Pauws
Erwin
Pauws
Emma Peskett
Emma
Peskett
Philip Stanier
Philip
Stanier
Lydia Teboul
Lydia
Teboul
Martina Hallegger
Martina
Hallegger
Andrea Calvo
Andrea
Calvo
Adriano Chiò
Adriano
Chiò
Adrian M Isaacs
Adrian M
Isaacs
Nicolas L Fawzi
Nicolas L
Fawzi
Eric Wang
Eric
Wang
David E Housman
David E
Housman
Francisco Baralle
Francisco
Baralle
Linda Greensmith
Linda
Greensmith
Emanuele Buratti
Emanuele
Buratti
Vincent Plagnol
Vincent
Plagnol
Elizabeth MC Fisher
Elizabeth MC
Fisher
Abraham Acevedo-Arozena
Abraham
Acevedo-Arozena
Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis
The Francis Crick Institute
2020
ALS
TDP‐43
cryptic exon
skiptic exon
splicing
Alternative Splicing
Amyotrophic Lateral Sclerosis
Animals
DNA-Binding Proteins
Exons
Gene Expression Regulation
Humans
Mice
Motor Neurons
Mutation
RNA Splicing
RNA-Binding Proteins
Ule - sec
06 Biological Sciences
08 Information and Computing Sciences
11 Medical and Health Sciences
Developmental Biology
2020-07-15 11:19:21
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Mice_with_endogenous_TDP-43_mutations_exhibit_gain_of_splicing_function_and_characteristics_of_amyotrophic_lateral_sclerosis/12652712
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.