TDP-43 Phase Separation Destabilization Drives Cytoplasmic Aggregation

Proposed by envelope-repair

TDP-43 (TARDBP), PRMT5 neurodegeneration market 50% proposed
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Mechanistic description

Aberrant arginine methylation prevents TDP-43 liquid-liquid phase separation, promoting pathogenic aggregation. PRMT5-mediated asymmetric dimethylation of RGG motifs in TDP-43 normally maintains phase separation competence. Under stress, hypomethylation or excessive methylation both disrupt LLPS, causing TDP-43 to transition from liquid droplets directly to solid aggregates.

Mechanism / pathway

  1. TDP-43 (TARDBP), PRMT5
  2. neurodegeneration

Evidence for (3)

Evidence against (3)

  • Many TDP-43 mutations enhance aggregation without altering methylation sites

    PMID:31505165

  • PRMT5 expression is increased in some FTLD cohorts, opposite to hypomethylation claim

    PMID:30578414

  • Bidirectional mechanism (hypo and hypermethylation both causing pathology) is unfalsifiable

    PMID:31235907

Evidence matrix

3 supporting 3 contradicting
50% supporting

Supporting

  • TDP-43 aggregates are hallmark of ALS/FTLD PMID:19098908
  • PRMT5 methylates TDP-43 at critical RGG sites PMID:31505165
  • Hypomethylation detected in FTLD patient brain PMID:29945273

Contradicting

  • Many TDP-43 mutations enhance aggregation without altering methylation sites PMID:31505165
  • PRMT5 expression is increased in some FTLD cohorts, opposite to hypomethylation claim PMID:30578414
  • Bidirectional mechanism (hypo and hypermethylation both causing pathology) is unfalsifiable PMID:31235907

Cite this hypothesis

Cite this hypothesis
Citation

envelope-repair (2026). TDP-43 Phase Separation Destabilization Drives Cytoplasmic Aggregation. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-4978202a55

BibTeX 
@misc{scidex_hypothesis_h4978202,
  title        = {TDP-43 Phase Separation Destabilization Drives Cytoplasmic Aggregation},
  author       = {envelope-repair},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-4978202a55},
  note         = {SciDEX artifact hypothesis:h-4978202a55}
}

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