1. Mice with endogenous <scp>TDP</scp> ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis
- Author
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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, and Housman, David E
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Genetics and Molecular Biology (all) ,0301 basic medicine ,TDP-43 ,Immunology and Microbiology (all) ,RNA-binding protein ,medicine.disease_cause ,Biochemistry ,Mice ,Exon ,0302 clinical medicine ,Molecular Biology of Disease ,News & Views ,Motor Neurons ,Mutation ,General Neuroscience ,RNA-Binding Proteins ,ALS ,cryptic exon ,skiptic exon ,splicing ,Neuroscience (all) ,Molecular Biology ,Biochemistry, Genetics and Molecular Biology (all) ,Articles ,Exons ,RNA Biology ,Cell biology ,DNA-Binding Proteins ,RNA splicing ,RNA Splicing ,Biology ,TARDBP ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,mental disorders ,medicine ,Animals ,Humans ,Loss function ,General Immunology and Microbiology ,Point mutation ,Amyotrophic Lateral Sclerosis ,Alternative splicing ,nutritional and metabolic diseases ,nervous system diseases ,TDP‐43 ,Alternative Splicing ,030104 developmental biology ,Gene Expression Regulation ,030217 neurology & neurosurgery ,Neuroscience - 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 "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. Keywords: ALS; cryptic exon; skiptic exon; splicing; TDP-43
- Published
- 2018
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