CREB-Mediated Differential CD55/CD46 Expression Creates Activity-Dependent Complement Vulnerability Maps
🧪 Overview
This hypothesis proposes that the CREB1-BDNF-TrkB activity-dependent transcriptional machinery directly controls the spatial expression patterns of complement regulators CD55 and CD46, creating synaptic vulnerability maps that determine which synapses are targeted for complement-mediated pruning. The mechanism operates through activity-dependent CREB1 phosphorylation at serine 133, which initiates transcription of both BDNF and complement regulator genes containing CRE sites. High-activity synapses with robust CREB activation maintain elevated CD55/CD46 expression, protecting them from complement attack through accelerated C3/C5 convertase decay and factor I-mediated C3b/C4b cleavage. Conversely, low-activity synapses exhibit reduced CREB-mediated transcription, leading to diminished CD55/CD46 surface density and increased complement vulnerability. This creates a molecular tagging system where synaptic activity history directly determines complement susceptibility. The BDNF-TrkB autocrine loop amplifies this effect through PI3K/Akt and Ras/MAPK pathways that enhance CREB-mediated complement regulator expression.
...🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["CD55 DAF, CD46 MCP<br/>Hypothesis Target"]
B["Complement<br/>Cited Mechanism"]
C["Cellular Response<br/>Stress or Clearance Change"]
D["Neural Circuit Effect<br/>Synapse/Glia Vulnerability"]
E["Neurodegeneration<br/>Disease-Relevant Outcome"]
A --> B
B --> C
C --> D
D --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style B fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — CREB1
No curated PDB or AlphaFold mapping for CREB1 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for CREB1, CD55, CD46 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 CREB1, CD55, CD46.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _schema_version | 1 |