ER-Associated Degradation (ERAD) Cross-Activation
🧪 Overview
Partial translation of intron-retained GBA transcripts produces misfolded peptide fragments that mislocalize to the ER membrane rather than entering the ER lumen, causing local ER stress. PERK dimerizes and auto-phosphorylates eIF2α, globally suppressing cap-dependent translation initiation. Since GBA translation requires efficient initiation due to its complex multi-domain structure, eIF2α-mediated repression disproportionately reduces GBA protein synthesis. ISRIB provides a direct pharmacological test of this mechanism.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["EIF2AK3 (PERK)<br/>Kinase"]
B["EIF2S1 (eIF2alpha)<br/>Translation Initiation"]
C["HSPA5 (BiP)<br/> chaperone"]
D["XBP1<br/>Unfolded Protein Response"]
E["ERAD<br/>Cross-Activation"]
F["Proteasomal<br/>Clearance Deficit"]
G["Synaptic<br/>Protein Dysregulation"]
H["Neurodegeneration<br/>Proteostasis Failure"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
G --> H
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — EIF2AK3
No curated PDB or AlphaFold mapping for EIF2AK3 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for EIF2AK3 (PERK), EIF2S1 (eIF2α); HSPA5 (BiP), XBP1 from GTEx v10.
💉 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 EIF2AK3 (PERK), EIF2S1 (eIF2α); HSPA5 (BiP), XBP1.
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 |
|---|---|---|---|---|
| IF primary fibroblasts or iPSC-derived neurons carrying pathogenic intron-retained GBA transcripts are treated with ISRIB (200 nM, 4-24 hours), THEN GBA protein levels will increase by >30% relative t | GBA protein abundance measured by quantitative western blot or targeted mass spectrometry will increase >30% in ISRIB-treated cells compared to vehicle controls | — no observation — | pending | 0.45 |
| IF HEK293T cells or patient-derived fibroblasts are transfected with PERK-targeting siRNA 48 hours prior to GBA intron-retention expression, THEN phospho-eIF2α levels will be reduced by >70% and GBA p | Phospho-eIF2α (SerS51) will be reduced >70% by western blot, and newly synthesized GBA protein measured by puromycin incorporation or S35-methionine pulse chase | — no observation — | pending | 0.38 |
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |