ID: h-2842eb0a8b
Hypothesis
C1q shows synapse-class-specific roles, with inhibitory versus excitatory synapses exhibiting different susceptibility to C1q-associated elimination
This hypothesis is biologically plausible and potentially important for circuit-level phenotypes, but current support is stronger for contextual selectivity than for distinct intrinsic C1q biochemical programs at inhibitory versus excita.
🧬 C1QA,C1QB,C1QC,GAD1,GAD2,SLC6A1,SLC17A7,ITGAM,ITGB2🩺 neurodegeneration🎯 Composite 53%💱 $0.53▼0.3%proposed
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 7 support✗ 2 oppose
✓ All Quality Gates Passed
🧪 Overview
This hypothesis is biologically plausible and potentially important for circuit-level phenotypes, but current support is stronger for contextual selectivity than for distinct intrinsic C1q biochemical programs at inhibitory versus excitatory terminals. It is more valuable for endpoint design and disease-stage interpretation than as a near-term therapeutic thesis.
🧬 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 Matrix7 supports2 contradicts
Supports
AD mouse models show cell-type and synapse-class selective engulfment, consistent with possible circuit-biased C1q vulnerability.
Supports
Complement-mediated synapse loss is established, leaving room for differential class susceptibility across circuits.
Supports
Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer's disease.
Supports
An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis.
Supports
Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.
Supports
Identification of crosstalk genes and immune characteristics between Alzheimer's disease and atherosclerosis.
Supports
Deciphering the preeclampsia-specific immune microenvironment and the role of pro-inflammatory macrophages at the maternal-fetal interface.
Contradicts
Observed selectivity may arise from network activity, anatomy, or glial preference rather than synapse-intrinsic C1q coding.
Contradicts
Evidence does not yet show fundamentally distinct C1q biochemical programs at inhibitory versus excitatory synapses.
📖 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,GAD1,GAD2,SLC6A1,SLC17A7,ITGAM,ITGB2 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,GAD1,GAD2,SLC6A1,SLC17A7,ITGAM,ITGB2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
Cost
$0
Timeline
—
🏆 Tournament
🏆 Arenas / Elo
No arena matches recorded yet. Browse Arenas →
📊 Market Indicators
7d Trend
↔
Stable
7d Momentum
▲ 0.0%
Volatility
Low
0.0087
Events (7d)
0
Price History
▼0.3%💾 Resource Usage
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 C1q is globally knocked out in mice from birth, THEN excitatory dendritic spine density will increase by >30% relative to wild‑type while inhibitory synapse puncta (GAD1+) remain unchanged at 8 wee | Excitatory spine density will be >30% higher in C1q KO vs WT; GAD1+ puncta will show <5% change. | — no observation — | pending | 0.55 |
| IF C1q is acutely overexpressed in adult mouse visual cortex via AAV for 4 weeks, THEN excitatory synapse density will decrease by >20% while inhibitory synapse density remains unchanged. | Excitatory synaptic markers (VGLUT1) will be reduced >20% and inhibitory markers (GAD1) will show <5% change. | — no observation — | pending | 0.60 |
🔮 Falsifiable Predictions (2)
pendingconf 60%
IF C1q is acutely overexpressed in adult mouse visual cortex via AAV for 4 weeks, THEN excitatory synapse density will decrease by >20% while inhibitory synapse density remains unchanged.
Predicted outcome: Excitatory synaptic markers (VGLUT1) will be reduced >20% and inhibitory markers (GAD1) will show <5% change.
Falsification: Excitatory synapse density reduction <5% or inhibitory synapse density also reduced by >10%, indicating no synapse-class specificity.
pendingconf 55%
IF C1q is globally knocked out in mice from birth, THEN excitatory dendritic spine density will increase by >30% relative to wild‑type while inhibitory synapse puncta (GAD1+) remain unchanged at 8 weeks of age.
Predicted outcome: Excitatory spine density will be >30% higher in C1q KO vs WT; GAD1+ puncta will show <5% change.
Falsification: Excitatory spine density increase <10% or inhibitory synapse density also increases by >10%, disproving class‑specific susceptibility.
▸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
Public annotations (0)Annotate on Hypothes.is →
No public annotations yet.