ID: hyp-sda-2026-04-01-gap-9137255b-3
Hypothesis
RNA Granule Phase Separation as Transient Cross-Seeding Hub
Liquid-liquid phase separation of RNA-binding proteins (TDP-43, FUS) creates membrane-less compartments where disease-specific stress conditions concentrate aggregation-prone sequences, enabling stochastic cross-seeding events with other.
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 3 oppose
✓ All Quality Gates Passed
🧪 Overview
Liquid-liquid phase separation of RNA-binding proteins (TDP-43, FUS) creates membrane-less compartments where disease-specific stress conditions concentrate aggregation-prone sequences, enabling stochastic cross-seeding events with other neurodegenerative proteins.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["Oxidative ER or Proteotoxic Stress<br/>Triggers Stress Granule Assembly"]
B["TDP-43 TARDBP LLPS<br/>Liquid-Liquid Phase Separation"]
C["FUS HNRNPA1 Co-Condensation<br/>RNA Granule Nucleation"]
D["High Local Protein Concentration<br/>Phase-Separated Compartment"]
E["Disease-Specific Misfolded Proteins<br/>SNCA Tau Imported into Granule"]
F["Cross-Seeding Template Formation<br/>Stochastic Nucleation Events"]
G["Insoluble Amyloid Transition<br/>Granule-to-Aggregate Maturation"]
H["ALS FTD Multi-Proteinopathy<br/>Propagation of Mixed Aggregates"]
A --> B
A --> C
B --> D
C --> D
D --> E
E --> F
F --> G
G --> H
style D fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix5 supports3 contradicts
Supports
TDP-43 condensation properties specify its RNA-binding and regulatory repertoire.
Supports
TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD.
Supports
TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A.
Contradicts
TDP-43 proteinopathies: a new wave of neurodegenerative diseases.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — TARDBP
💉 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.
No DepMap CRISPR Chronos data found for TARDBP.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF TDP-43 liquid-liquid phase separation is disrupted via phosphomimetic/super-resolution microscopy validation of LLPS-deficient TDP-43 mutants, THEN co-localization and co-aggregation of TDP-43 with | ≥50% reduction in co-aggregation events between mutant TDP-43 and tau/α-synuclein in stress granules, as measured by fluorescence correlation spectroscopy and s | — no observation — | pending | 0.75 |
| IF disease-specific stress conditions (oxidative stress, potassium depletion, or proteasome inhibition) that promote TDP-43 granule formation are applied, THEN tau and α-synuclein will be detected wit | ≥30% of TDP-43 stress granules will contain detectable tau or α-synuclein (measured by fluorescence intensity above cytoplasmic baseline), with biochemical conf | — no observation — | pending | 0.80 |
🔮 Falsifiable Predictions (2)
pendingconf 80%
IF disease-specific stress conditions (oxidative stress, potassium depletion, or proteasome inhibition) that promote TDP-43 granule formation are applied, THEN tau and α-synuclein will be detected within TDP-43-positive stress granules at levels significantly above background, using a cellular model
Predicted outcome: ≥30% of TDP-43 stress granules will contain detectable tau or α-synuclein (measured by fluorescence intensity above cytoplasmic baseline), with bioche
Falsification: If neurodegenerative proteins fail to partition into TDP-43-positive granules under any tested stress condition, showing no increase over random distribution, this would disprove the hypothesis that s
pendingconf 75%
IF TDP-43 liquid-liquid phase separation is disrupted via phosphomimetic/super-resolution microscopy validation of LLPS-deficient TDP-43 mutants, THEN co-localization and co-aggregation of TDP-43 with other neurodegenerative proteins (tau, α-synuclein) in stress granules will be significantly reduce
Predicted outcome: ≥50% reduction in co-aggregation events between mutant TDP-43 and tau/α-synuclein in stress granules, as measured by fluorescence correlation spectros
Falsification: If LLPS-disrupted TDP-43 mutants still show equivalent or greater co-aggregation with tau/α-synuclein compared to wild-type TDP-43 under identical stress conditions, this would disprove that phase sep
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesis
| source | v1_phase_c_backfill |
| origin_type | debate_synthesis |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
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Incoming
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Outgoing
0
0 supporting
0 contradicting
0 neutral
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