Engineered proteins to capture shed soluble TREM2 and facilitate membrane re-insertion or prevent proteolytic cleavage
Curated pathway from expert analysis
flowchart TD
A["Surface TREM2 on Microglia<br/>Phagocytic Receptor"]
B["ADAM10 and ADAM17 Shedding<br/>Ectodomain Proteolytic Cleavage"]
C["Soluble TREM2 Released to CSF<br/>Non-Signaling Truncated Fragment"]
D["Microglial Surface TREM2 Depleted<br/>Reduced Phagocytic Signaling"]
E["Engineered Capture Proteins<br/>High Affinity sTREM2 Binding"]
F["Membrane Re-Insertion Facilitated<br/>or ADAM Shedding Prevented"]
G["Surface TREM2 Restored<br/>TYROBP-SYK Signaling Recovered"]
H["Microglial Phagocytic Capacity<br/>Amyloid Clearance Restored"]
A --> B
B --> C
B --> D
D -.->|"insufficient signaling"| H
C --> E
E --> F
F --> G
G --> H
style D fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style H fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for ['TREM2'] yet. Search RCSB →
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 ['TREM2'].
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF engineered proteins designed to sterically block TREM2 cleavage sites (mutant TREM2-Fc with substrate-mimicking linker) are co-expressed with wild-type TREM2 in HEK293 cells THEN proteolytic cleava | Significantly reduced intensity of ~20 kDa sTREM2 band in conditioned media Western blot; sTREM2 concentration <40% of control levels by ELISA | — no observation — | pending | 0.70 |
| IF engineered TREM2-sequestration proteins (e.g., TREM2-Fc fusion with membrane-targeting domain) are applied to TREM2-expressing microglial cell cultures THEN membrane-associated TREM2 levels will in | Increased surface TREM2 immunofluorescence intensity and Western blot signal from surface-biotinylated fractions; reduced sTREM2 concentration in media measured | — no observation — | pending | 0.75 |