Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43
作者： Magdalini Polymenidou , Clotilde Lagier-Tourenne , Kasey R Hutt , Stephanie C Huelga , Jacqueline Moran
DOI: 10.1038/NN.2779
关键词: Molecular biology 、 Precursor mRNA 、 Alternative splicing 、 Intron 、 Three prime untranslated region 、 Untranslated region 、 RNA-binding protein 、 RNA 、 RNA splicing 、 Biology
摘要: 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 protein that, when mutated, causes amyotrophic lateral sclerosis. Massively parallel splicing-sensitive junction arrays revealed that levels of 601 mRNAs were changed (including Fus (Tls), progranulin other transcripts encoding neurodegenerative disease-associated proteins) 965 altered splicing events detected sortilin, receptor progranulin) following depletion TDP-43 from mouse adult antisense oligonucleotides. RNAs whose most depleted by reduction derived very long introns encode proteins involved synaptic activity. Lastly, we found autoregulates its synthesis, part directly enhancing intron 3' untranslated region own transcript, thereby triggering nonsense-mediated degradation.
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