Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation

Topic: Brain proteins, microglia and lab models

TDP-43 is a primarily nuclear RNA-binding protein, whose abnormal phosphorylation and cytoplasmic aggregation characterizes affected neurons in patients with amyotrophic lateral sclerosis and frontotemporal dementia. Here, we report that physiological nuclear TDP-43 in mouse and human brain forms homo-oligomers that are resistant to cellular stress. Physiological TDP-43 oligomerization is mediated by its N-terminal domain, which can adopt dynamic, solenoid-like structures, as revealed by a 2.1 Å crystal structure in combination with nuclear magnetic resonance spectroscopy and electron microscopy. These head-to-tail TDP-43 oligomers are unique among known RNA-binding proteins and represent the functional form of the protein in vivo, since their destabilization results in loss of alternative splicing regulation of known neuronal RNA targets. Our findings indicate that N-terminal domain-driven oligomerization spatially separates the adjoining highly aggregation-prone, C-terminal low-complexity domains of consecutive TDP-43 monomers, thereby preventing low-complexity domain inter-molecular interactions and antagonizing the formation of pathologic aggregates.TDP-43 aggregation is observed in amyotrophic lateral sclerosis. Here the authors combine X-ray crystallography, nuclear magnetic resonance and electron microscopy studies and show that physiological oligomerization of TDP-43 is mediated through its N-terminal domain, which forms functional and dynamic oligomers antagonizing pathologic aggregation.

@article{afroz2017-28663553,
  author  = {Afroz, T. and Hock, E. M. and Ernst, P. and Foglieni, C. and Jambeau, M. and Gilhespy, L. A. B. and Laferriere, F. and Maniecka, Z. and others},
  title   = {{Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation}},
  journal = {Nature communications},
  year    = {2017},
  doi     = {10.1038/s41467-017-00062-0},
  pmid    = {28663553},
  url     = {https://doi.org/10.1038/s41467-017-00062-0}
}

Key findings

• Physiological TDP-43 oligomerization is mediated by its N-terminal domain, which can adopt dynamic, solenoid-like structures, as revealed by a 2.1 Å crystal structure in combination with nuclear magnetic resonance spectroscopy and electron microscopy.
• These head-to-tail TDP-43 oligomers are unique among known RNA-binding proteins and represent the functional form of the protein in vivo, since their destabilization results in loss of alternative splicing regulation of known neuronal RNA targets.
• Our findings indicate that N-terminal domain-driven oligomerization spatially separates the adjoining highly aggregation-prone, C-terminal low-complexity domains of consecutive TDP-43 monomers, thereby preventing low-complexity domain inter-molecular interactions and antagonizing the formation of pathologic aggregates.TDP-43 aggregation is observed in amyotrophic lateral sclerosis.

Why it matters

This study found that normal TDP-43 forms oligomers in the brain that prevent the formation of pathologic aggregates. It is a laboratory study and does not test any treatment or prevention for Alzheimer's disease, so it has no direct implications for treating, curing, or preventing the disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s41467-017-00062-0
• PubMed: 28663553
• Original source →
• Free full text: Nature Communications →

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Studies this one cites

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

• 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
• Characterizing the RNA targets and position-dependent splicing regulation by TDP-43 Nature neuroscience · 2011-02-27 · usefulness score 61/100 · 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
• 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
• Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization Cell · 2015-09-01 · usefulness score 56/100 · Lewy body dementia
• TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity The Journal of biological chemistry · 2009-05-22 · usefulness score 53/100 · Lewy body dementia
• TDP-43 is recruited to stress granules in conditions of oxidative insult Journal of neurochemistry · 2009-09-16 · usefulness score 51/100 · Lewy body dementia
• TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor Molecular and cellular biology · 2010-12-20 · usefulness score 47/100 · Lewy body dementia

Later studies that cite this one

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

• Structure of pathological TDP-43 filaments from ALS with FTLD Nature · 2021-12-08 · usefulness score 58/100 · 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
• Stress granules and neurodegeneration Nature reviews. Neuroscience · 2019-10-03 · usefulness score 55/100 · Lewy body dementia
• RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43 Neuron · 2019-02-27 · usefulness score 53/100 · Lewy body dementia
• Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization Molecular cell · 2018-08-09 · usefulness score 53/100 · Lewy body dementia
• Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain Nature Communications · 2025-11-26 · usefulness score 52/100 · Brain tissue and pathology
• Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation The EMBO journal · 2022-02-03 · usefulness score 52/100 · Brain tissue and pathology
• The role of liquid-liquid phase separation in aggregation of the TDP-43 low-complexity domain The Journal of biological chemistry · 2019-02-27 · usefulness score 50/100 · Lewy body dementia

Related studies in Lewy body dementia

• 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
• Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS PLoS biology · 2011-04-26 · usefulness score 52/100
• Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs Nature neuroscience · 2012-09-30 · usefulness score 56/100
• Structural and functional insights into the selective inhibition of mutant tau aggregation by purpurin and oleocanthal in frontotemporal dementia Protein Science · 2025-08-27 · usefulness score 37/100
• Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease The Journal of cell biology · 2007-11-01 · usefulness score 55/100
• Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure The Journal of biological chemistry · 2001-10-17 · usefulness score 47/100

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1,150 studies in the library carry the topic tag “tdp-43”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,150 tagged studies.

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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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