Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain

Topic: Brain proteins, microglia and lab models

Pathological inclusions of the C-terminal domain (CTD) of TAR DNA binding protein-43 (TDP-43) are neurodegenerative hallmarks in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, yet CTD's aggregation propensity complicates structural characterization of native TDP-43. Here we propose structural models for the physiological multimerization of TDP-43 CTD's conserved region (CR) essential for TDP-43 RNA processing. Using NMR spectroscopy, we establish that the native state of TDP-43 CR at physiological conditions is α-helical. Hydrophobic residues drive CR helix-helix assembly, phase separation, and TDP-43 nuclear retention, while polar residues down regulate these processes. An integrative approach combining analytical ultracentrifugation, NMR-derived contacts, AlphaFold2-Multimer modeling, and all-atom molecular dynamics simulations together suggest that TDP-43 CR forms dynamic, multimeric helical assemblies stabilized by a methionine-rich core with specific contributions from a tryptophan/leucine pair. These structures show how ALS-associated mutations disrupt TDP-43 function and provide pharmacologically targetable structures to prevent its conversion into pathogenic β-sheet aggregates.

Key findings

• An integrative approach combining analytical ultracentrifugation, NMR-derived contacts, AlphaFold2-Multimer modeling, and all-atom molecular dynamics simulations together suggest that TDP-43 CR forms dynamic, multimeric helical assemblies stabilized by a methionine-rich core with specific contributions from a tryptophan/leucine pair.

Why it matters

Using NMR spectroscopy and modeling, this study proposes structural models of how the conserved region of the TDP-43 C-terminal domain multimerizes, and suggests these structures could be pharmacologically targetable to prevent conversion into pathogenic aggregates. This is early structural laboratory work with no treatment tested in people.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s41467-025-65546-w
• PubMed: 41298366
• Original source →
• Free full text: Nature Communications →

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

@article{rizuan2025-41298366,
  author  = {Rizuan, Azamat and Shenoy, Jayakrishna and Mohanty, Priyesh and dos Passos, Patricia M. and Ortiz, José F. Mercado and Bai, Leanna and Viswanathan, Renjith and Zaborowksy, Julia and others},
  title   = {{Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain}},
  journal = {Nature Communications},
  year    = {2025},
  doi     = {10.1038/s41467-025-65546-w},
  pmid    = {41298366},
  url     = {https://doi.org/10.1038/s41467-025-65546-w}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 14.

• Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report Brain : a journal of neurology · 2019-06-01 · usefulness score 67/100 · Prevention and risk
• 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
• Structure of pathological TDP-43 filaments from ALS with FTLD Nature · 2021-12-08 · usefulness score 58/100 · Lewy body dementia
• Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity The EMBO journal · 2017-08-08 · usefulness score 57/100 · Lewy body dementia
• Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations Neuron · 2014-02-01 · usefulness score 55/100 · Lewy body dementia
• Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation Nature communications · 2017-06-29 · usefulness score 55/100 · Lewy body dementia
• Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation The Journal of biological chemistry · 2008-02-27 · usefulness score 53/100 · 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
• The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease Brain research · 2012-01-21 · usefulness score 52/100 · Lewy body dementia
• 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
• TAR DNA-binding protein 43 in neurodegenerative disease Nature reviews. Neurology · 2010-03-16 · usefulness score 49/100 · Lewy body dementia

Later studies that cite this one

1 study in the alzhub library lists this one in its references.

• TDP-43: [GU]-ardian of the transcriptome Molecular Neurodegeneration · 2026-05-14 · usefulness score 42/100 · Brain tissue and pathology

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• Limbic-predominant Age-related TDP-43 Encephalopathy and Distinct Longitudinal Profiles of Domain-specific Literacy Alzheimer disease and associated disorders · 2020 · usefulness score 64/100
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