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 Maza, Alan Mejia 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 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. 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
    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