ID: h-0ca883fab0
Hypothesis
C1q has spatially distinct functions, with synapse-bound C1q primarily nucleating complement-dependent pruning and microglia-associated C1q potentially modulating effector state through receptor-speci
The strongest spatial model is a split between substrate marking at synapses and state modulation at microglia.
🧬 C1QA,C1QB,C1QC,C4A,C4B,C3,ITGAM,ITGB2,LAIR1🩺 neurodegeneration🎯 Composite 63%💱 $0.57▼10.1%proposed
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 3 support✗ 2 oppose
✓ All Quality Gates Passed
🧪 Overview
The strongest spatial model is a split between substrate marking at synapses and state modulation at microglia. The synaptic arm is well grounded, but the microglial surface-signaling arm remains insufficiently demonstrated in CNS microglia and must be tested under complement-defined conditions that isolate location from ligand identity and microglial state.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["Stressed Synapse<br/>C1q Ligand Exposed"]
B["C1q Deposition<br/>Synaptic Tagging"]
C["C3 Cleavage<br/>C3b Opsonization"]
D["CR3 Recognition<br/>Microglial Receptor"]
E["Synaptic Pruning<br/>Phagocytic Engulfment"]
F["Synapse Loss<br/>Circuit Disruption"]
G["Cognitive Decline<br/>Memory Impairment"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix3 supports2 contradicts
Supports
Synaptic C1q/C3/CR3 pruning is strongly supported in development and disease models, consistent with a location-specific synaptic function.
Supports
Microglial CR3-mediated engulfment downstream of synaptic complement deposition supports a substrate-marking role for synaptic C1q.
Supports
Noncanonical C1q receptor signaling exists in myeloid cells, making a microglial signaling arm biologically plausible.
Contradicts
Direct evidence for a distinct cascade-independent microglial surface-signaling program driven by C1q in resident CNS microglia is limited.
Contradicts
Apparent location effects may instead arise from unmeasured ligand identity, complement fragment exposure, or pre-existing microglial state.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — C1QA
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for C1QA,C1QB,C1QC,C4A,C4B,C3,ITGAM,ITGB2,LAIR1 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 C1QA,C1QB,C1QC,C4A,C4B,C3,ITGAM,ITGB2,LAIR1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
Cost
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Timeline
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📊 Market Indicators
7d Trend
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Stable
7d Momentum
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Volatility
Low
0.0030
Events (7d)
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Price History
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LLM Tokens
19,754
$0.0593
Total Cost
$0.0593
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF microglia-specific C1q is deleted using Cx3cr1-CreERT2 while neuronal/astrocyte C1q is preserved, THEN microglial activation markers (CD68, MHCII) and pro-inflammatory cytokine profiling will show | Significant reduction in CD68+ phagocytic microglia and decreased IL-1β/TNF-α transcript levels in the hippocampus of microglia-C1q KO mice compared to controls | — no observation — | pending | 0.55 |
| IF LAIR1 is selectively blocked on microglia via anti-LAIR1 Fab fragments while complement C3 is simultaneously inhibited, THEN microglial process dynamics and arbor complexity will remain altered (in | LAIR1 blockade + C3 inhibition will result in impaired microglial process velocity (>30% reduction) and reduced branch complexity (Sholl analysis) while synapti | — no observation — | pending | 0.40 |
🔮 Falsifiable Predictions (2)
pendingconf 55%
IF microglia-specific C1q is deleted using Cx3cr1-CreERT2 while neuronal/astrocyte C1q is preserved, THEN microglial activation markers (CD68, MHCII) and pro-inflammatory cytokine profiling will show significant alteration compared to C1q-flox controls, within 3 months post-tamoxifen induction in 5x
Predicted outcome: Significant reduction in CD68+ phagocytic microglia and decreased IL-1β/TNF-α transcript levels in the hippocampus of microglia-C1q KO mice compared t
Falsification: No change in microglial activation state or cytokine profile when microglia-specific C1q is deleted; microglial state remains dependent on non-microglial C1q sources only.
pendingconf 40%
IF LAIR1 is selectively blocked on microglia via anti-LAIR1 Fab fragments while complement C3 is simultaneously inhibited, THEN microglial process dynamics and arbor complexity will remain altered (indicating receptor-specific signaling) while synaptic complement tagging and engulfment remain suppre
Predicted outcome: LAIR1 blockade + C3 inhibition will result in impaired microglial process velocity (>30% reduction) and reduced branch complexity (Sholl analysis) whi
Falsification: Blocking LAIR1 reproduces the same pruning phenotype as C3 inhibition, indicating LAIR1 operates downstream of complement rather than as a separate microglial state modulator.
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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