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Mice with endogenous <scp>TDP</scp> ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis
- Source :
- The EMBO Journal, EMBRO Press
- Publication Year :
- 2018
- Publisher :
- EMBO, 2018.
-
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
- Subjects :
- 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
Subjects
Details
- ISSN :
- 14602075 and 02614189
- Volume :
- 37
- Database :
- OpenAIRE
- Journal :
- The EMBO Journal
- Accession number :
- edsair.doi.dedup.....9d557cc26637b8b4264f70b21760dc09
- Full Text :
- https://doi.org/10.15252/embj.201798684