Dominant-Negative Spliceosome Titration
🧪 Overview
Intron-retained GBA transcripts sequester core spliceosomal components (U2AF65, SF3B1, PRPF8) and snRNPs, reducing the available pool for wild-type GBA pre-mRNA processing. This cis-trans interference causes inefficient removal of downstream introns, producing additional aberrant transcripts with PTCs that are degraded by NMD, establishing a positive feedback loop that progressively depletes mature GBA mRNA and protein. The mechanism explains why a minority aberrant isoform disproportionately affects protein output beyond simple haploinsufficiency.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["U2AF2 / SF3B1 / PRPF8<br/>Spliceosome Components"]
B["Dominant-Negative<br/>Spliceosome Titration"]
C["Alternative Splicing<br/>Dysregulation"]
D["Non-Productive<br/>mRNA Splicing"]
E["Protein<br/>Dosage Imbalance"]
F["Neurodegeneration<br/>ALS / FTD"]
G["Stress Granule<br/>Formation"]
A --> B
B --> C
B --> D
C --> E
D --> E
E --> F
F --> G
style A fill:#6a1b9a,stroke:#ce93d8,color:#ce93d8
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — U2AF2
No curated PDB or AlphaFold mapping for U2AF2 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for U2AF2, SF3B1, PRPF8; splicing snRNPs 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 U2AF2, SF3B1, PRPF8; splicing snRNPs.
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 spliceosome dysfunction is a causal driver of neurodegeneration, then restoring splicing fidelity (e.g., with PRPF8, SF3B1 overexpression, or spliceosome assembly factors) will rescue synaptic func | iPSC-derived neurons from neurodegeneration patients with spliceosome component deficiency (U2AF2, SF3B1 mutations) show restored splicing patterns (RNA-seq con | — no observation — | pending | 0.70 |
| If dominant-negative spliceosome titration (U2AF2/SF3B1/PRPF8 dysfunction) drives neurodegeneration through splicing dysregulation, then neurons exposed to spliceosome inhibitors will accumulate mis-s | Primary cortical neurons treated with spliceosome inhibitor (pladienolide B, 1-10 nM, 48h) show: >50% of genes with altered splicing (RNA-seq, >30% with extende | — no observation — | pending | 0.74 |
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |