TDP-43 regulates its mRNA levels through a negative feedback loop

Topic: Brain proteins, microglia and lab models

TAR DNA-binding protein (TDP-43) is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) involved in RNA processing, whose abnormal cellular distribution and post-translational modification are key markers of certain neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We generated human cell lines expressing tagged forms of wild-type and mutant TDP-43 and observed that TDP-43 controls its own expression through a negative feedback loop. The RNA-binding properties of TDP-43 are essential for the autoregulatory activity through binding to 3' UTR sequences in its own mRNA. Our analysis indicated that the C-terminal region of TDP-43, which mediates TDP-43-hnRNP interactions, is also required for self-regulation. TDP-43 binding to its 3' UTR does not significantly change the pre-mRNA splicing pattern but promotes RNA instability. Moreover, blocking exosome-mediated degradation partially recovers TDP-43 levels. Our findings demonstrate that cellular TDP-43 levels are under tight control and it is likely that disease-associated TDP-43 aggregates disrupt TDP-43 self-regulation, thus contributing to pathogenesis.

Key findings

• Our analysis indicated that the C-terminal region of TDP-43, which mediates TDP-43-hnRNP interactions, is also required for self-regulation.
• TDP-43 binding to its 3' UTR does not significantly change the pre-mRNA splicing pattern but promotes RNA instability.
• Our findings demonstrate that cellular TDP-43 levels are under tight control and it is likely that disease-associated TDP-43 aggregates disrupt TDP-43 self-regulation, thus contributing to pathogenesis.

Why it matters

In human cell lines, TDP-43, a protein whose abnormal location and modification mark ALS and frontotemporal lobar degeneration, limits its own production by binding the 3′ UTR of its own mRNA and making that RNA unstable rather than changing how it is spliced. The authors propose that disease-associated TDP-43 clumps "likely" disrupt this self-regulation. This is cell-based work that does not test a treatment, and the record does not discuss Alzheimer's disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/emboj.2010.310
• PubMed: 21131904
• Original source →
• Free full text: The EMBO Journal →

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

@article{ayala2011-21131904,
  author  = {Ayala, Y. M. and De Conti, L. and Avendaño-Vázquez, S. E. and Dhir, A. and Romano, M. and D'Ambrogio, A. and Tollervey, J. and Ule, J. and others},
  title   = {{TDP-43 regulates its mRNA levels through a negative feedback loop}},
  journal = {The EMBO journal},
  year    = {2011},
  doi     = {10.1038/emboj.2010.310},
  pmid    = {21131904},
  url     = {https://doi.org/10.1038/emboj.2010.310}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 13.

• 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
• Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases Acta neuropathologica · 2007-07-25 · usefulness score 59/100 · How common it is
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease Annals of neurology · 2007-05-01 · usefulness score 56/100 · Lewy body dementia
• Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice The Journal of neuroscience : the official journal of the Society for Neuroscience · 2010-08-01 · usefulness score 53/100 · Lewy body dementia
• TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration Proceedings of the National Academy of Sciences of the United States of America · 2009-10-15 · usefulness score 52/100 · Lewy body dementia
• TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration Proceedings of the National Academy of Sciences of the United States of America · 2010-02-03 · usefulness score 52/100 · Lewy body dementia
• Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies Journal of neuropathology and experimental neurology · 2008-06-01 · usefulness score 51/100 · Lewy body dementia
• TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations Journal of neuropathology and experimental neurology · 2007-02-01 · usefulness score 49/100 · Brain tissue and pathology
• Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies Brain research · 2007-10-25 · usefulness score 49/100 · How common it is
• A Drosophila model for TDP-43 proteinopathy Proceedings of the National Academy of Sciences of the United States of America · 2010-01-26 · usefulness score 49/100 · Brain tissue and pathology
• TDP-43 is a developmentally regulated protein essential for early embryonic development The Journal of biological chemistry · 2009-12-29 · usefulness score 47/100 · Lewy body dementia

Later studies that cite this one

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

• 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
• Characterizing the RNA targets and position-dependent splicing regulation by TDP-43 Nature neuroscience · 2011-02-27 · usefulness score 61/100 · 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
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• 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
• TDP-43 Pathology in Alzheimer's Disease Molecular neurodegeneration · 2021-12-20 · usefulness score 56/100 · Lewy body dementia
• Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death Neuron · 2019-03-07 · usefulness score 56/100 · Lewy body dementia

Related studies in Lewy body dementia

• Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations Neuron · 2014-02-01 · usefulness score 55/100
• Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 Nature · 2006-07-16 · usefulness score 61/100
• C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins Science (New York, N.Y.) · 2014-08-07 · usefulness score 58/100
• Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein Proceedings of the National Academy of Sciences of the United States of America · 2009-07-27 · usefulness score 56/100
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• TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets 2015 · Brain tissue and pathology
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