RNA-binding protein condensate maturation from reversible phase separation to amyloid-like aggregation should produce a measurable proximal phenotype before late disease pathology. The decisive test is time-resolved iPSC motor-neuron perturbations combining RNA stoichiometry, PTM mapping, live-cell condensate tracking, and cryo-electron tomography.
Curated pathway from expert analysis
flowchart TD
A["FUS/TDP-43 Stress Granule Dynamics<br/>Low Complexity Domain Driven"]
B["Aberrant Phase Separation<br/>Pathological Condensate Formation"]
C["Ribonucleoprotein Granule Maturation<br/>Solid-like Aggregate Transition"]
D["ALS FTD Pathology Spread<br/>Cell-to-Cell Propagation of Aggregates"]
E["Motor Neuron RNA Homeostasis<br/>Translation and Splicing Collapse"]
F["Synaptic Failure and Neuronal Loss<br/>ALS Disease Progression"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#4a148c,stroke:#ce93d8,color:#ce93d8
style F 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 FUS.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we treat iPSC-derived motor neurons harboring the ALS-associated FUS P525L mutation with 20 µM 1,6-hexanediol for 7 days to disperse reversible FUS condensates, THEN we will observe a significant r | A ≥50% decrease in Thioflavin T signal and a ≥30% reduction in the number of FUS puncta displaying amyloid-like morphology as measured by quantitative live-cell | — no observation — | pending | 0.65 |
| IF we overexpress a C9orf72 repeat RNA that binds FUS in iPSC-derived motor neurons for 14 days to increase RNA:protein stoichiometry, THEN we will observe accelerated conversion of FUS condensates fr | FRAP recovery half-life decreases from ~10 s to <5 s and Thioflavin T intensity increases >2-fold relative to control. | — no observation — | pending | 0.60 |