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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“Alterations specifically affected long genes including transcripts with TDP-43 binding sites, concor-dant with prior experimental data showing the preferential binding of TDP-43 to long introns (LagierTourenne et al., 2012; Polymenidou et al., 2011; Tollervey et al., 2011).”
Background
SHAPE reveals transcript-wide interactions, complex structural domains, and protein interactions across the Xist lncRNA in living cells
Smola, M. J., Christy, T. W., Inoue, K., Nicholson, C. O., Friedersdorf, M. B., Keene, J. D., Lee, D. M., Calabrese, J. M., & Weeks, K. M. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1600008113 · Cited by 226
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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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