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Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43
Open accessAbstract
We used cross-linking and immunoprecipitation coupled with high-throughput sequencing to identify binding sites in 6,304 genes as the brain RNA targets for TDP-43, an RNA binding protein that, when mutated, causes amyotrophic lateral sclerosis. Massively parallel sequencing and splicing-sensitive junction arrays revealed that levels of 601 mRNAs were changed (including Fus (Tls), progranulin and other transcripts encoding neurodegenerative disease-associated proteins) and 965 altered splicing events were detected (including in sortilin, the receptor for progranulin) following depletion of TDP-43 from mouse adult brain with antisense oligonucleotides. RNAs whose levels were most depleted by reduction in TDP-43 were derived from genes with very long introns and that encode proteins involved in synaptic activity. Lastly, we found that TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in the 3' untranslated region of its own transcript, thereby triggering nonsense-mediated RNA degradation.
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“Both the ALS-associated mutations and the changes in wild-type TDP43 expression alter a large programme of alternative exons in mutant mice170,174,175.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [170]
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“However, less than a quarter of affected exons are shared between the transgenic and RNA interference-depletion mouse models.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [170]
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Metadata
- Authors
- Polymenidou, M., Lagier-Tourenne, C., Hutt, K. R., Huelga, S. C., Moran, J., Liang, T. Y., Ling, S.-C., Sun, E., Wancewicz, E., Mazur, C., Kordasiewicz, H., Sedaghat, Y., Donohue, J. P., Shiue, L., Bennett, C. F., Yeo, G. W., & Cleveland, D. W.
- Affiliations
- University of California San Diego (US)
- Ionis Pharmaceuticals (United States) (US)
- University of California, Santa Cruz (US)
- Corresponding author
- Yeo, Gene W
- Cleveland, Don W
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2011-02-27
- Volume
- 14
- Issue
- 4
- Pages
- 459-468
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC3094729
- OpenAlex
- W2101042581
- Cited by
- 1,335
- References
- 51
- Citations by year
- 2026: 71 · 2025: 112 · 2024: 116 · 2023: 84 · 2022: 76 · 2021: 85 · 2020: 74 · 2019: 85 · 2018: 84 · 2017: 83 · 2016: 72 · 2015: 78 · 2014: 79 · 2013: 86 · 2012: 99
- FWCI
- 63.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (089701)
- National Human Genome Research Institute (HG004659, R01HG004659)
- National Institute of General Medical Sciences (R01GM084317, GM084317)
- National Institute of Neurological Disorders and Stroke (R37 NS 27036, R37NS027036)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- TDP-43, amyotrophic lateral sclerosis, RNA-binding proteins, RNA splicing, long introns, neuronal vulnerability, nonsense-mediated mRNA decay, 3' untranslated region, progranulin, sortilin, FUS, synaptic proteins, antisense oligonucleotides, brain transcriptome, neurodegeneration
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, DNA-Binding Proteins, Female, Homeostasis, Humans, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Neurons, RNA Precursors, RNA, Messenger, Oligonucleotides, Antisense, Alternative Splicing, 3' Untranslated Regions, Mice
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