🧪
hypothesis

TDP-43 Phase Separation Destabilization Drives Cytoplasmic Aggregation

Hypothesis

TDP-43 Phase Separation Destabilization Drives Cytoplasmic Aggregation

Aberrant arginine methylation prevents TDP-43 liquid-liquid phase separation, promoting pathogenic aggregation.
🧬 TDP-43 (TARDBP), PRMT5🩺 neurodegeneration🎯 Composite 50%💱 $0.51▲1.6%proposed
EvidencePending (0%)📖 0 cit🗣 1 debates 3 support 3 oppose
✓ All Quality Gates Passed
Mechanistic 0.45 (15%) Evidence 0.58 (15%) Novelty 0.80 (12%) Feasibility 0.35 (12%) Impact 0.50 (12%) Druggability 0.32 (10%) Safety 0.28 (8%) Competition 0.55 (6%) Data Avail. 0.60 (5%) Reproducible 0.42 (5%) KG Connect 0.50 (8%) 0.500 composite
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arXiv PreprintNeurIPSNature MethodsPLOS ONE
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🧪 Overview

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

No curated mechanism pathway recorded for this hypothesis.

⚖️ Evidence

⚖️ Evidence Matrix3 supports3 contradicts
Supports
TDP-43 aggregates are hallmark of ALS/FTLD
PMID:19098908
Supports
PRMT5 methylates TDP-43 at critical RGG sites
PMID:31505165
Supports
Hypomethylation detected in FTLD patient brain
PMID:29945273
Contradicts
Many TDP-43 mutations enhance aggregation without altering methylation sites
PMID:31505165
Contradicts
PRMT5 expression is increased in some FTLD cohorts, opposite to hypomethylation claim
PMID:30578414
Contradicts
Bidirectional mechanism (hypo and hypermethylation both causing pathology) is unfalsifiable
PMID:31235907
📖 Linked Papers

No linked papers recorded for this hypothesis yet.

🏥 Translation

🧬 3D Protein Structure — TDP-43

No curated PDB or AlphaFold mapping for TDP-43 yet. Search RCSB →

💉 Clinical Trials

No clinical trials data linked to this hypothesis yet.

No curated ClinVar variants loaded for this hypothesis.

Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.

🔍 Search ClinVar for TDP-43 (TARDBP), PRMT5 →

No DepMap CRISPR Chronos data found for TDP-43 (TARDBP), PRMT5.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

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🏆 Arenas / Elo

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💾 Resource Usage

No resource usage or linked notebooks recorded for this hypothesis yet.

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