CHIP E3 Ligase Enhancement to Target Synaptic Proteins for Degradation
Curated pathway from expert analysis
flowchart TD
A["Misfolded Tau and APP<br/>Accumulation in Neurons"]
B["Hsp70 Chaperone<br/>Client Recognition"]
C["CHIP/STUB1 E3 Ligase<br/>Cochaperone Binding"]
D["Polyubiquitin Chain<br/>K48-linkage tagging"]
E["26S Proteasome<br/>Substrate Delivery"]
F["Protein Aggregate<br/>Clearance"]
G["Synaptic Protein<br/>Quality Control"]
H["Neuroprotection<br/>Reduced AD pathology"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
G --> H
style C fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for CHIP yet. Search RCSB →
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 CHIP.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF primary hippocampal neurons are treated with a blood-brain barrier-penetrant CHIP activator (compound dose 10mg/kg IP, twice daily for 7 days), THEN quantitative targeted proteomics (MRM) will dete | ≥40% reduction in GRIA1 and GRIA2 in synaptosomal fraction (p<0.01, Student's t-test), with no significant change in presynaptic marker synaptophysin, measured | — no observation — | pending | 0.55 |
| IF human iPSC-derived cortical neurons are transduced with CHIP/STUB1 overexpression lentivirus (≥3x endogenous levels), THEN quantitative immunoblot will show ≥50% reduction in PSD-95/DLG4 protein wi | ≥50% decrease in PSD-95 (DLG4) protein level with concurrent accumulation of high-molecular-weight ubiquitinated species, measurable by western blot with normal | — no observation — | pending | 0.65 |