USP14 Inhibition to Accelerate Proteasomal Degradation of Synaptic Substrates
Curated pathway from expert analysis
flowchart TD
A["USP14 Deubiquitinase<br/>19S Regulatory Cap Binding"]
B["Polyubiquitin Chain Trimming<br/>Substrate Premature Release"]
C["Proteasome Gating<br/>Reduced Throughput and Stalling"]
D["Tau and TDP-43 Accumulation<br/>Proteostasis Collapse"]
E["IU1 / IU1-47 Inhibitor<br/>USP14 Pharmacological Block"]
F["Enhanced Proteasomal Flux<br/>Synaptic Substrate Clearance"]
A --> B
B --> C
C --> D
E -.->|"inhibits"| A
E --> F
F -.->|"reduces"| D
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style E fill:#1b5e20,stroke:#81c784,color:#81c784
style F fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for USP14 yet. Search RCSB →
Median TPM across 13 brain regions for USP14 (ubiquitin-specific peptidase 14) 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 USP14 (ubiquitin-specific peptidase 14).
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF USP14 is knocked down via siRNA transfection in neuronal cell lines (e.g., SH-SY5Y) for 72 hours, THEN proteasome-dependent degradation of ubiquitinated synaptic proteins will increase by ≥40% comp | Increased rate of synaptic protein degradation (≥40% acceleration) following USP14 knockdown | — no observation — | pending | 0.55 |
| IF cultured primary neurons are treated with the selective USP14 inhibitor IU1 (50 μM) for 24 hours, THEN levels of synaptic substrate proteins (e.g., GluA1, PSD-95, synapsin) will decrease by ≥25% co | Decreased synaptic protein abundance (≥25% reduction) following USP14 inhibition | — no observation — | pending | 0.65 |