RNA-Binding Protein Sequestration and 3′UTR Dysregulation
🧪 Overview
Intron-retained GBA isoform sequesters neuronal RBPs (FMRP, HuR, TDP-43) that normally bind to wild-type GBA mRNA 3′UTR regulatory elements. Loss of RBP engagement disrupts poly(A) tail elongation, reduces miRNA protection, impairs dendritic localization, and causes wild-type GBA mRNA to be sequestered in P-bodies or undergo accelerated decay. TDP-43 aggregation observed in GBA-PD brains represents a high-value convergence target with ASO programs already in ALS clinical trials.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["ELAVL1 (HuR)<br/>RNA-Binding Protein"]
B["FMR1 (FMRP)<br/>Translational Regulator"]
C["TARDBP (TDP-43)<br/>Nuclear Clearance"]
D["GW182 Silencing<br/>miRNA Pathway"]
E["3'UTR<br/>Dysregulation"]
F["mRNA Stability<br/>Loss"]
G["Synaptic<br/>Dysfunction"]
H["Neurodegeneration<br/>ALS / FTD"]
A --> D
B --> D
C --> D
D --> E
E --> F
F --> G
G --> H
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style B fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style C fill:#6a1b9a,stroke:#ce93d8,color:#ce93d8
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — ELAVL1
No curated PDB or AlphaFold mapping for ELAVL1 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for ELAVL1 (HuR), FMR1 (FMRP), TARDBP (TDP-43); GW182 (TNRC6A) 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 ELAVL1 (HuR), FMR1 (FMRP), TARDBP (TDP-43); GW182 (TNRC6A).
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 RNA-binding protein sequestration (HuR, FMRP, TDP-43) and 3'UTR dysregulation drive neurodegeneration, then neurons with RBP aggregates will show increased 3'UTR lengthening in synaptic transcripts | In postmortem AD/ALS cortex (n≥30), neurons with TDP-43 or HuR aggregates show >50% of synaptic transcripts with extended 3'UTRs (MAMPseq), elevated AGO2 co-imm | — no observation — | pending | 0.75 |
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |