ArticleThe EMBO journal2022
Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation.
Article in The EMBO journal, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 119 papers.
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Who cites it
119 citing papers in PubMed, 179 citations in OpenAlex.
- Biomolecular coacervation-mediated materials: Phase states, phase transitions, and biomedical applications.Bioactive materials · 2027Review
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- FUS controls muscle differentiation through phase separation-mediated recruitment of the transcription factors MEF2 and ETV5.The EMBO journal · 2026Article
- Aberrant phase separation from a rare ABI3 mutation drives microglial dysfunction and Alzheimer's risk.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- TDP-43 proteinopathy as a biomarker and therapeutic target in amyotrophic lateral sclerosis.Biochemical Society transactions · 2026Review
- TGF-β signaling promotes astroglial activation and TDP-43 proteinopathy in organoid models of frontotemporal lobar degeneration.The Journal of clinical investigation · 2026Article
- Pathogenicity Classification ofCells · 2026Article
- Protein Disulfide Isomerase Disassembles TDP-43/G3BP1 Condensates and Antagonizes TDP-43 Pathological Aggregates.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Concentration-dependent cytoplasmic phase separation of TDP-43 drives aggregation and proteinopathy.The FEBS journal · 2026Article
- TDP-43 Aggregation: The Healthy-Toxic Balance of the Prion-Like Domain.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Mapping interactions between disordered regions reveals promiscuity in biomolecular condensate formation.Nature communications · 2026Article
- Phosphorylation Mimicking Mutations Cause TDP-43 to Adopt Different Fibril Conformations.bioRxiv : the preprint server for biology · 2026Article
- Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.BMC medicine · 2026Review
- TDP-43: [GU]-ardian of the transcriptome.Molecular neurodegeneration · 2026Review
- Molecular Modulation of the Crosstalk Between TDP-43 and SOD1.International journal of molecular sciences · 2026Article
- Dilute but Dense - Reversible Crosslinking Enables Water-Rich (Bio)polymer Condensates.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The dynamic and heterogeneous composition of biomolecular condensates and its functional relevance.Nature reviews. Molecular cell biology · 2026Review
- Article
- Scaffold-client behavior and structural organization in multicomponent protein condensates as revealed by studying tau/TDP-43 droplets.Communications chemistry · 2026Article
- Stress granules as a central hub linking organelle stress, aging, and neurodegeneration.BMB reports · 2026Review
59 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Post-translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis and frontotemporal dementia, the RNA-binding protein TAR DNA-binding protein (TDP-43), is hyperphosphorylated in disease on several C-terminal serine residues, a process generally believed to promote TDP-43 aggregation. Here, we however find that Casein kinase 1δ-mediated TDP-43 hyperphosphorylation or C-terminal phosphomimetic mutations reduce TDP-43 phase separation and aggregation, and instead render TDP-43 condensates more liquid-like and dynamic. Multi-scale molecular dynamics simulations reveal reduced homotypic interactions of TDP-43 low-complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP-43, but suppress accumulation of TDP-43 in membrane-less organelles and promote its solubility in neurons. We speculate that TDP-43 hyperphosphorylation may be a protective cellular response to counteract TDP-43 aggregation.
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Registered trials
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