GRN/progranulin lysosomal insufficiency across FTD, ALS-spectrum stress, and AD inflammation
🧪 Overview
Shared mechanism across FTD, ALS, AD: Progranulin insufficiency causes tau-negative, ubiquitin-positive FTD and weakens lysosomal handling in neurons and microglia. That lysosomal/microglial deficit can sensitize TDP-43 proteinopathy in ALS-spectrum disease and intensify AD inflammatory damage even when GRN is not the initiating lesion.
Falsifiable prediction: Restoring progranulin should improve lysosomal acidification and reduce TDP-43 or amyloid-induced microglial cytokine output by at least 20% across GRN-FTD neurons, TDP-43 ALS neurons, and AD microglia co-cultures.
Proposed experiment: Compare recombinant progranulin, GRN gene augmentation, and control treatment in GRN-haploinsufficient cortical neurons, TDP-43 motor-neuron cultures, and AD microglia-neuron co-cultures; assay cathepsin activity, lysosomal pH, TDP-43 aggregation, cytokines, and neuronal survival.
Cross-disease confidence rationale: Direct FTD genetics with mechanistic extension through TDP-43/microglial lysosomal biology.
Internal SciDEX support: SciDEX support query found 17 matching hypotheses across 5 disease labels, including 17 with debate_count > 0.
🧬 Mechanism
Auto-built from this analysis's top knowledge-graph edges.
graph TD
GRN["GRN"] -->|cross disease mech| FTD["FTD"]
GRN_1["GRN"] -->|cross disease mech| ALS["ALS"]
GRN_2["GRN"] -->|cross disease mech| AD["AD"]
h_cross_synth_grn_lysosom["h-cross-synth-grn-lysosomal-microglia"] -->|proposes shared me| GRN_3["GRN"]
style GRN fill:#4fc3f7,stroke:#333,color:#000
style FTD fill:#ef5350,stroke:#333,color:#000
style GRN_1 fill:#4fc3f7,stroke:#333,color:#000
style ALS fill:#ef5350,stroke:#333,color:#000
style GRN_2 fill:#4fc3f7,stroke:#333,color:#000
style AD fill:#ef5350,stroke:#333,color:#000
style h_cross_synth_grn_lysosom fill:#4fc3f7,stroke:#333,color:#000
style GRN_3 fill:#4fc3f7,stroke:#333,color:#000⚖️ Evidence
🏥 Translation
🔮 Predicted Protein Structure — GRN
💉 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 GRN.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| Restoring progranulin should improve lysosomal acidification and reduce TDP-43 or amyloid-induced microglial cytokine output by at least 20% across GRN-FTD neurons, TDP-43 ALS neurons, and AD microgli | If this mechanism is real, then Restoring progranulin should improve lysosomal acidification and reduce TDP-43 or amyloid-induced microglial cytokine output by | — no observation — | pending | 0.68 |
▸Metadatasource: v1_phase_c_backfill · origin_type: cross_disease_synthesis
| source | v1_phase_c_backfill |
| origin_type | cross_disease_synthesis |
| _schema_version | 1 |