Characterising the RNA targets and position-dependent splicing regulation by TDP-43; implications for neurodegenerative diseases

By James R. Tollervey, Tomaž Curk, B. Rogelj, M. Briese, Matteo Cereda, M. Kayikci, T. Hortobágyi, A. Nishimura, Vera Župunski, R. Patani and 5 more. Nature Neuroscience, 2011

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TDP-43 is a predominantly nuclear RNA-binding protein that forms inclusion bodies in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The mRNA targets of TDP-43 in the human brain and its role in RNA processing are largely unknown. Using individual nucleotide-resolution ultraviolet cross-linking and immunoprecipitation (iCLIP), we found that TDP-43 preferentially bound long clusters of UG-rich sequences in vivo. Analysis of RNA binding by TDP-43 in brains from subjects with FTLD revealed that the greatest increases in binding were to the MALAT1 and NEAT1 noncoding RNAs. We also found that binding of TDP-43 to pre-mRNAs influenced alternative splicing in a similar position-dependent manner to Nova proteins. In addition, we identified unusually long clusters of TDP-43 binding at deep intronic positions downstream of silenced exons. A substantial proportion of alternative mRNA isoforms regulated by TDP-43 encode proteins that regulate neuronal development or have been implicated in neurological diseases, highlighting the importance of TDP-43 for the regulation of splicing in the brain.

Subfields: Genetics, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/b064d129795868e2cbd34fce986ef95a6fb20059

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Berislav Zlokovic

Citations in the corpus

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).”
Alternative Splicing Regulatory Networks: Functions, Mechanisms, and Evolution. (2019, background): “For instance, Nova, PTBP1, or TDP-43 tend to repress exon inclusion when their binding overlaps an exon or splice site, but activate splicing when bound to intronic sequences downstream of the 5 ́ splice site (Llorian et al., 2010; Tollervey et al., 2011; Ule et al., 2006; Xue et al., 2009) (Figure ”
UMI-tools: modeling sequencing errors in Unique Molecular Identifiers to improve quantification accuracy (2017, neutral): “Pipelines are available at https://GitHub.com/CGATOxford/UMI-tools_pipelines and as Supplemental File 2. iCLIP RawsequencewasobtainedfromtheEuropeanNucleotideArchive(accessionsSRP059277andERR039854)(Tollerveyetal.2011; Müller-McNicoll et al. 2016).”
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].”
ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now? (2019, background): “…functions as a regulator of gene expression and is involved in several RNA processing steps with roles in premRNA splicing, regulation of mRNA stability, mRNA transport, translation, and the regulation of non-coding RNAs (Buratti and Baralle, 2010; Tollervey et al., 2011; Ratti and Buratti, 2016).”
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis (2019, background): “In 2006, TDP-43 was identified as a key component of the insoluble and ubiquitinated inclusions in the brains of patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD or FTLD-TDP) diseases (Arai et al., 2006; Neumann et al., 2006).”
RBPmap: a web server for mapping binding sites of RNA-binding proteins (2014, methodology): “Finally, the test was performed for 10 different RBPs including five hnRNPs (32), PTB (33), both generated using hits-clip experiment, TDP43 from I-CLIP (34) and QKI (9), HuR (9) and PUM2 (9) from PAR-CLIP.”