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.
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:#ef9a9aNo linked papers recorded for this hypothesis yet.
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.
| 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 |