Cystatin C directly protects neurons against excitotoxicity through LRP2 (megalin) receptor engagement and AKT/ERK survival signaling. Critical weaknesses: neuronal LRP2 expression is technically challenging to detect and primarily studied in developmental contexts; systemic cystatin C must cross both BBB and neuronal membrane to engage LRP2—a two-membrane traversal problem with low probability.
Curated pathway from expert analysis
flowchart TD
A["Amyloid-beta Plaques<br/>Phospholipid Ligands"]
B["TREM2 Receptor<br/>Ligand Binding"]
C["TYROBP/DAP12<br/>ITAM Phosphorylation"]
D["SYK Kinase<br/>Activation"]
E["PLCG2<br/>IP3 + DAG Generation"]
F["Ca2+ Release<br/>Cytoskeletal Remodeling"]
G["Microglial Phagocytosis<br/>Plaque Compaction"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for CST3 yet. Search RCSB →
Median TPM across 13 brain regions for CST3/LRP2/AKT/ERK 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 CST3.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF primary cortical neurons are subjected to LRP2 CRISPR knockout, THEN exogenously applied cystatin C will fail to protect against NMDA-induced excitotoxicity compared to wild-type neurons, with at l | LDH release ≤20% in WT+cystatin C vs ≥40% in LRP2-KO+cystatin C; MTT viability ≥70% in WT+cystatin C vs ≤40% in LRP2-KO+cystatin C | — no observation — | pending | 0.45 |
| IF adult mice receive neuron-specific LRP2 knockout (CamKII-Cre;LRP2flox), THEN systemic cystatin C administration (1mg/kg/day i.p. for 7 days) will fail to reduce cerebral infarct volume following 60 | Infarct volume reduction of ≥35% in WT mice receiving cystatin C vs vehicle; no significant reduction (<15%) in neuronal LRP2-KO mice receiving cystatin C | — no observation — | pending | 0.38 |