Cited by 1,335Amyotrophic Lateral Sclerosis ResearchRNA Research and SplicingAlzheimer's disease research and treatments

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Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43

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Polymenidou, Magdalini, Lagier-Tourenne, Clotilde, Hutt, Kasey R, Huelga, Stephanie C, Moran, Jacqueline, Liang, Tiffany Y, Ling, Shuo-Chien, Sun, Eveline, Wancewicz, Edward, Mazur, Curt, Kordasiewicz, Holly, Sedaghat, Yalda, Donohue, John Paul, Shiue, Lily, Bennett, C Frank, Yeo, Gene W, Cleveland, Don W·2011·Nature Neuroscience

DOI 10.1038/nn.2779PMC PMC3094729

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Abstract

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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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: Polymenidou, Magdalini
Hutt, Kasey R
Liang, Tiffany Y
Ling, Shuo-Chien
Mazur, Curt
Kordasiewicz, Holly
Shiue, Lily
Bennett, C Frank
Yeo, Gene W
Cleveland, Don W
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2011-02-27
Volume: 14
Issue: 4
Pages: 459-468
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/nn.2779
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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Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43

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