FRAP-based measurement of TDP-43 liquid-liquid phase separation state provides a continuous biomarker of nuclear-cytoplasmic compartmentalization. Endogenous TDP-43-eGFP knock-in in iPSC neurons enables longitudinal monitoring; orthogonal validation via mAb414 nuclear pore integrity anchors imaging to ultrastructure. Primary constraint is imaging endpoint gap—two-photon FRAP is not deployable in standard trials; PET ligand development is the critical path to clinical utility.
Curated pathway from expert analysis
flowchart TD
A["TARDBP/TDP-43<br/>Nuclear RNA-Binding Protein"]
B["Stress or Mutation<br/>ALS/FTD Trigger"]
C["TDP-43 Mislocalization<br/>Cytoplasmic Accumulation"]
D["Nuclear TDP-43 Depletion<br/>Cryptic Exon Inclusion"]
E["TDP-43 Aggregates<br/>Ubiquitin+ Phospho+ Inclusions"]
F["Splicing Dysregulation<br/>STMN2/UNC13A Targets"]
G["Synaptic Failure<br/>Motor Neuron Degeneration"]
A --> B
B --> C
C --> D
C --> E
D --> F
E --> G
F --> G
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style C fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for TARDBP (TDP-43 protein); IPO4/IP09 (nuclear import receptors as secondary targets) from GTEx v10.
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 (TDP-43 protein); IPO4.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF nuclear-cytoplasmic TDP-43 compartmentalization is quantified via orthogonal mAb414 immunostaining and eGFP FRAP in iPSC neurons derived from ALS/FTLD patients versus age-matched controls, THEN pat | Cohort difference: FRAP t½ ≥25s in patient group vs. ≤18s in controls; mAb414 nuclear integrity score inversely correlated with cytoplasmic TDP-43 mislocalizati | — no observation — | pending | 0.70 |
| IF IPO4 nuclear import receptor agonist (50 μM PYR-41 or equivalent small molecule) is applied to TDP-43-eGFP knock-in iPSC neurons for 72 hours, THEN mean FRAP recovery half-time will decrease by ≥30 | FRAP recovery half-time: intervention ≤14s vs. vehicle ≥20s (Cohen's d ≥0.8); mobile fraction increased by ≥15%. | — no observation — | pending | 0.65 |