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

Topic: Brain proteins, microglia and lab models

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.

Key findings

• 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.

Why it matters

In human brain tissue, this laboratory study mapped where the protein TDP-43 binds RNA. It found a preference for "long clusters of UG-rich sequences", and in brains from people with frontotemporal lobar degeneration (FTLD) the largest increases in binding were to two noncoding RNAs, MALAT1 and NEAT1. The authors report that TDP-43 binding "influenced alternative splicing" depending on where it bound, and they link the affected genes to neuronal development and neurological disease. The work concerns FTLD and ALS, not Alzheimer's disease, and it tests no treatment, test or prevention.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/nn.2778
• PubMed: 21358640
• Original source →
• Free full text: PubMed Central →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{tollervey2011-21358640,
  author  = {Tollervey, JR. and Curk, T. and Rogelj, B. and Briese, M. and Cereda, M. and Kayikci, M. and König, J. and Hortobágyi, T. and others},
  title   = {{Characterizing the RNA targets and position-dependent splicing regulation by TDP-43}},
  journal = {Nature neuroscience},
  year    = {2011},
  doi     = {10.1038/nn.2778},
  pmid    = {21358640},
  url     = {https://doi.org/10.1038/nn.2778}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis Science · 2008-02-28 · usefulness score 64/100 · Disease mechanisms
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration Human molecular genetics · 2010-04-15 · usefulness score 56/100 · Lewy body dementia
• Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies The Journal of biological chemistry · 2009-01-21 · usefulness score 51/100 · Lewy body dementia
• TDP-43 regulates its mRNA levels through a negative feedback loop The EMBO journal · 2010-12-03 · usefulness score 51/100 · Lewy body dementia

Later studies that cite this one

53 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration Nature neuroscience · 2019-01-14 · usefulness score 62/100 · Lewy body dementia
• Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies Science (New York, N.Y.) · 2023-03-16 · usefulness score 60/100 · Brain tissue and pathology
• The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity Nature medicine · 2016-06-27 · usefulness score 58/100 · Lewy body dementia
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia The Journal of clinical investigation · 2020-11-01 · usefulness score 57/100 · Brain tissue and pathology
• TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD Science (New York, N.Y.) · 2015-08-01 · usefulness score 57/100 · Lewy body dementia

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• ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43 Proceedings of the National Academy of Sciences of the United States of America · 2013-02-04 · usefulness score 53/100
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