mutant FUS effects split between motor-neuron intrinsic stress and glial/NMJ inflammatory signaling should produce a measurable proximal phenotype before late disease pathology. The decisive test is isogenic motor-neuron, astrocyte, and microglia chimeric co-cultures with NMJ formation and denervation readouts.
Curated pathway from expert analysis
flowchart TD
A["Mutant FUS Expression<br/>ALS-Linked FUS R521C/G Mutations"]
B["Motor Neuron Intrinsic Stress<br/>Nuclear Import Disruption, Cytoplasmic aggregates"]
C["Glial/NMJ Inflammatory Signaling<br/>TNF-a, IL-1beta, Complement Cascade"]
D["NMJ Synapse Stability Loss<br/>Synaptic Stripping at Neuromuscular Junction"]
E["Retrograde Axonal Degeneration<br/>Distal Axon Repair Failure"]
F["Fast vs Slow Motor Neuron Split<br/>Selective Vulnerability Pattern"]
G["ALS Progression<br/>Combined Cell-Intrinsic and Non-Cell-Autonomous Damage"]
A --> B
A --> C
B --> D
C --> D
D --> E
E --> F
F --> G
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style G 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 CRISPR/Cas9 is used to introduce patient-derived ALS/FTD mutant FUS (e.g., R521C) selectively into motor neurons within isogenic human iPSC-derived tri-culture (motor neurons, astrocytes, microglia | Motor neuron ROS increase >50% (MitoSox fluorescence) and >30% NMJ denervation rate (AChR cluster fragmentation) at day 14 post-differentiation in mutant vs wil | — no observation — | pending | 0.72 |
| IF pharmacological blockade of TNF-α/IL-1β inflammatory signaling (e.g., via XPro1595 or anakinra) is applied selectively to glial compartment in mutant FUS tri-culture with established NMJ, THEN NMJ | >40% reduction in NMJ denervation rate (AChR fragmentation) and >30% improvement in motor neuron survival (cleaved caspase-3/TUJ1+ quantification) with anti-inf | — no observation — | pending | 0.65 |