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- Title
Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43.
- Authors
Polymenidou, Magdalini; Lagier-Tourenne, Clotilde; Hutt, Kasey R.; Huelga, Stephanie C; Moran, Jacqueline; Tiffany Y. Liang; Shuo-Chien Ling; Sun, Eveline; Wancewicz, Edward; Mazur, Curt; Kordasiewicz, Holly; Sedaghat, Yalda; Donohue, John Paul; Shiue, Lily; Bennett, C. Frank; Yeo, Gene W.; Cleveland, Don W.
- 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.
- Subjects
RNA splicing; MESSENGER RNA; NEURODEGENERATION; CARRIER proteins; GENES; AMYOTROPHIC lateral sclerosis; OLIGONUCLEOTIDES; LABORATORY mice
- Publication
Nature Neuroscience, 2011, Vol 14, Issue 4, p459
- ISSN
1097-6256
- Publication type
Article
- DOI
10.1038/nn.2779