Back to Search
Start Over
TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A
- Source :
- Nature, 603(7899), 131-137. Nature Publishing Group, Nature, vol 603, iss 7899, NYGC ALS Consortium 2022, ' TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A ', Nature, vol. 603, no. 7899, pp. 131-137 . https://doi.org/10.1038/s41586-022-04436-3, Nature, 603(7899), 131-+. NATURE PORTFOLIO
- Publication Year :
- 2022
- Publisher :
- The Francis Crick Institute, 2022.
-
Abstract
- Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1–3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.
- Subjects :
- General Science & Technology
Gene Expression
Nerve Tissue Proteins
Neurodegenerative
Biochemistry & Proteomics
Rare Diseases
Ecology,Evolution & Ethology
Clinical Research
mental disorders
Acquired Cognitive Impairment
Genetics
Humans
2.1 Biological and endogenous factors
Polymorphism
Aetiology
Codon
Medicinsk genetik
NYGC ALS Consortium
Computational & Systems Biology
Chemical Biology & High Throughput
Multidisciplinary
Prevention
FOS: Clinical medicine
Stem Cells
Amyotrophic Lateral Sclerosis
Neurosciences
nutritional and metabolic diseases
Single Nucleotide
Brain Disorders
nervous system diseases
DNA-Binding Proteins
Alternative Splicing
Nonsense
TDP-43 Proteinopathies
Frontotemporal Dementia
Neurological
Dementia
ALS
Medical Genetics
Genetics & Genomics
Neurovetenskaper
Structural Biology & Biophysics
Subjects
Details
- ISSN :
- 00280836
- Database :
- OpenAIRE
- Journal :
- Nature, 603(7899), 131-137. Nature Publishing Group, Nature, vol 603, iss 7899, NYGC ALS Consortium 2022, ' TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A ', Nature, vol. 603, no. 7899, pp. 131-137 . https://doi.org/10.1038/s41586-022-04436-3, Nature, 603(7899), 131-+. NATURE PORTFOLIO
- Accession number :
- edsair.doi.dedup.....94a25848cce9d1ba10e3d3a48fd3e242
- Full Text :
- https://doi.org/10.25418/crick.19345568