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Nat Neurosci. 2011 Apr;14(4):459-68. doi: 10.1038/nn.2779. Epub 2011 Feb 27.

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

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  • 1Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California, USA.

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.

PMID:
21358643
[PubMed - indexed for MEDLINE]
PMCID:
PMC3094729
Free PMC Article
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