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

Abstract:

: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.

journal_name

Nat Neurosci

journal_title

Nature neuroscience

authors

Tollervey JR,Curk T,Rogelj B,Briese M,Cereda M,Kayikci M,König J,Hortobágyi T,Nishimura AL,Zupunski V,Patani R,Chandran S,Rot G,Zupan B,Shaw CE,Ule J

doi

10.1038/nn.2778

subject

Has Abstract

pub_date

2011-04-01 00:00:00

pages

452-8

issue

4

eissn

1097-6256

issn

1546-1726

pii

nn.2778

journal_volume

14

pub_type

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