期刊
NATURE NEUROSCIENCE
卷 14, 期 4, 页码 452-U180出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.2778
关键词
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资金
- European Research Council [206726-CLIP]
- Slovenian Research Agency [P2-0209, J2-2197, L2-1112, Z7-3665]
- Wellcome Trust
- MRC [089701/Z/09/Z]
- Motor Neuron Disease Association
- Heaton-Ellis Trust
- Psychiatry Research Trust
- MRC [MC_U105185858] Funding Source: UKRI
- Medical Research Council [MC_U105185858, G0700711B, G0500289B] Funding Source: researchfish
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.
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