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

By M. Polymenidou, C. Lagier-Tourenne, Kasey R. Hutt, Stephanie C. Huelga, Jacqueline T. Moran, Tiffany Y. Liang, Shuo-Chien Ling, E. Sun, E. Wancewicz, C. Mazur and 7 more. Nature Neuroscience, 2011

1,299 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/cd18b5f0ccbc43c75510f97f741cccdd207edfaa

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Citations in the corpus

• GFOLD: a generalized fold change for ranking differentially expressed genes from RNA-seq data (2012, neutral): “The five datasets are as follows: human brain dataset downloaded from DDBJ (Kaminuma et al. , 2011) with accession number SRA009447, mouse brain dataset (Polymenidou et al. , 2011) downloaded from DDBJ with accession number SRA030347, Type I latency B-cell line dataset (Xu et al. , 2010) downloaded…”
• Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis (2013, neutral): “Transport of ubiquinated proteins to proteasome polyubiquitin p62 UBQLN2 misfolded proteins Target specification for autophagy LC3 LC3 LC3 adaptor adaptor phagophore p62 p62 OPTN Sorting endosomal cargo for degradation CHMP2B ESCRT III cell membrane protein ubiquitin to autophagy protein aggregates ”
• Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB (2013, background): “MALAT1 interacts with several pre-mRNA splicing factors including serine arginine dipeptide-containing SR family splicing factors [46,47,48,49,50,51].”
• Axonal transport of TDP-43 mRNA granules in neurons is impaired by ALS-causing mutations (2014, positive): “TDP-43 binds to thousands of mRNAs, many of which are important in brain development and synaptic function, but regulates alternative splicing of a small subset of these (Polymenidou et al., 2011; Tollervey et al., 2011; Xiao et al., 2011).”
• Stress granules as crucibles of ALS pathogenesis (2013, background): “For example, although for the most part FUS and TDP-43 control the splicing of different pre-mRNAs (Polymenidou et al., 2011; Lagier-Tourenne et al., 2012), there are a small number of genes whose expression levels depend on TDP-43 or FUS, including PARK2, KCNIP4, and SMYD3, which are essential for…”
• Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis (2019, background): “Two ALS-associated mutations in TDP-43, Q331K, and M337V, have also been shown to alter mRNA splicing processes in a transgenic mice model (Polymenidou et al., 2011, 2012; Lagier-Tourenne et al., 2012; Arnold et al., 2013). mRNA Maturation and Stability By binding with mRNA transcripts, TDP-43…”