Characterizing the RNA targets and position-dependent splicing regulation by TDP-43

2011/02/27 by James Tollervey, Tomaž Curk, Boris Rogelj +13 · 6 citations
Medicine · Biochemistry, Genetics and Molecular Biology · #Amyotrophic Lateral Sclerosis Research #RNA Research and Splicing #Neurogenetic and Muscular Disorders Research #RNA splicing #RNA-binding protein #Frontotemporal lobar degeneration #Alternative splicing #Exon #Biology #Gene isoform #RNA #Messenger RNA #Cell biology #Molecular biology #Genetics #Gene #Frontotemporal dementia #Medicine

paper · doi:10.1038/nn.2778

openalex publication_date 2011/02/27 · openalex created_date 2016/06/24 · openalex updated_date 2026/08/05

Abstract

TDP-43 is a RNA-binding protein that forms inclusion bodies in ALS. The authors show that TDP-43 preferentially binds long clusters of UG-rich sequences and that TDP-43 binding on pre-mRNAs influences alternative splicing. Many alternative mRNA isoforms regulated by TDP-43 encode proteins that regulate neuronal development or are implicated in neurological diseases. 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.

Citations

• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
• Characterization and Functional Implications of the RNA Binding Properties of Nuclear Factor TDP-43, a Novel Splicing Regulator ofCFTR Exon 9
• Mechanisms of Alternative Pre-Messenger RNA Splicing
• iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution
• TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration

Cited by

• Mapping Argonaute and conventional RNA-binding protein interactions with RNA at single-nucleotide resolution using HITS-CLIP and CIMS analysis
• Analysis of CLIP and iCLIP methods for nucleotide-resolution studies of protein-RNA interactions
• Mapping in vivo protein-RNA interactions at single-nucleotide resolution from HITS-CLIP data
• CLIP and complementary methods
• TDP-43 condensation properties specify its RNA-binding and regulatory repertoire
• Cross-linking immunoprecipitation [wikipedia]

Related

• TDP-43 directly inhibits RNA accumulation in neurites through modulation of RNA stability
• Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD
• Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection
• TDP-43 dysfunction leads to the accumulation of cryptic transposable element-derived exons, crypTEs, in iPSC derived neurons and ALS/FTD patient tissues
• Divergent TDP43-regulated and TDP43-independent cryptic splicing in the cortex and spinal cord