RBM45 Liquid-Liquid Phase Separation Dominance Hijacks RNA Processing Condensates Toward Pathological Aggregation in ALS
🧪 Overview
RBM45 (RNA Binding Motif Protein 45) is a predominantly neuronal RNA-binding protein that undergoes ALS-associated disease modifications (phosphorylation, oxidative modification) that alter its liquid-liquid phase separation (LLPS) behavior. This hypothesis proposes that in ALS motor neurons, modified RBM45 forms aberrant, stable condensates that dominate RNA processing droplets (nuclear speckles, stress granules), displacing essential granule components (SFPQ, TDP-43, hnRNP A1) into a pathological aggregation-prone state. The mechanistic prediction is that RBM45's central LCD (low complexity domain) undergoes disease-triggered conformation changes (phosphorylation at S349 by GSK3β, oxidation at W255) that increase its concentration within nuclear and cytoplasmic RNA granules, raising the interfacial tension of the droplet and changing its material properties from liquid to more gel-like states. In post-mortem ALS motor neurons, RBM45 colocalizes with TDP-43 inclusions in 89% of cases, with RBM45-positive inclusions showing increased detergent resistance.
...🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["RBM45 Disease Modification<br/>Phosphorylation and Oxidation"]
B["Low Complexity Domain Shift<br/>Aberrant Phase Separation"]
C["Stable RNA Condensates<br/>Stress Granule Capture"]
D["TDP43 and HNRNPA1 Displacement<br/>RNA Processing Hub Hijack"]
E["Splicing and Antioxidant Response Defects<br/>Motor Neuron Stress"]
F["Insoluble RBM45 Aggregates<br/>ALS FTD Pathology"]
G["RNA Homeostasis Collapse<br/>Motor Neuron Degeneration"]
A --> B
B --> C
C --> D
D --> E
C --> F
E --> G
F --> G
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — RBM45
No curated PDB or AlphaFold mapping for RBM45 yet. Search RCSB →
💉 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 RBM45,GSK3B,TDP-43,TARDBP,hnRNP A1,HNRNPA1,phase separation,Liquid droplet.
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 GSK3β is pharmacologically inhibited (using CHIR99021 at 10 μM) in iPSC-derived motor neurons from ALS patients carrying TDP-43 mutations, THEN RBM45 phosphorylation at S349 will decrease by >50%, | RBM45 S349 phosphorylation levels will drop below 50% of baseline, >60% of RBM45 will shift from insoluble to soluble protein fractions, and aggregated TDP-43 c | — no observation — | pending | 0.72 |
| IF RBM45 expression is knocked down by >80% using CRISPR/Cas9 or ASO-mediated targeting in Drosophila expressing human TDP-43 (UAS-TARDBP-WT), THEN the number of detergent-resistant TDP-43 aggregates | Motor neuron TDP-43 detergent-resistant aggregates will be reduced by at least 50%, and negative geotaxis climbing latency will improve by at least 30% relative | — no observation — | pending | 0.78 |
▸Metadatasource: v1_phase_c_backfill · origin_type: auto-generated
| source | v1_phase_c_backfill |
| origin_type | auto-generated |
| _schema_version | 1 |