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

James Robert Tollervey (1) , Tomaž Curk (1) , Boris Rogelj (1) , Michael Briese (1) , Matteo Cereda (1) , Melis Kayikci (1) , Tibor Hortobagyi (1) , Agnes L Nishimura (1) , Vera Zupunski (1) , Rickie Patani (1) , Siddharthan Chandran (1) , Gregor Rot (1) , Blaž Zupan (1) , Christiopher E Shaw (1) , Jernej Ule (1)

1 Structural Studies

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 UV-crosslinking and immunoprecipitation (iCLIP), we demonstrated that TDP-43 preferentially binds long clusters of UG-rich sequences in vivo. Analysis of TDP-43 RNA binding in FTLD-TDP brains revealed the greatest increases in binding to MALAT1 and NEAT1 non-coding RNAs. We also showed that TDP-43 binding on pre-mRNAs influences 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 significant proportion of alternative mRNA isoforms regulated by TDP-43 encode proteins that regulate neuronal development or are implicated in neurological diseases, highlighting the importance of TDP-43 for splicing regulation in the brain.

Mots clés: Neurodegeneration; Neurological Disorders; Computational Neuroscience; Development

James Robert Tollervey, Tomaž Curk, Boris Rogelj, Michael Briese, Matteo Cereda, et al.. Characterising the RNA targets and position-dependent splicing regulation by TDP-43; implications for neurodegenerative diseases.. Nature Neuroscience, 2011, ⟨10.1038/nn.2778⟩. ⟨hal-00617340⟩