ID: h-a3f785df
Hypothesis
Sonic hedgehog pathway compartmentalization as quantitative biomarker for neuronal polarity defects
FRET-based cAMP sensors (Epac1-camps) targeted to primary cilium (ARL13B anchor) and synaptic compartment (PSD95 anchor) provide ratiometric read-out of compartmentalized signaling.
🧬 ADCY3 (adenylate cyclase), ARL13B (ciliary targeting), GNAI1/GNAI3 (GPCR signaling)🩺 neuroscience🎯 Composite 49%💱 $0.54▼4.1%proposed
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 3 support✗ 4 oppose
✓ All Quality Gates Passed
🧪 Overview
FRET-based cAMP sensors (Epac1-camps) targeted to primary cilium (ARL13B anchor) and synaptic compartment (PSD95 anchor) provide ratiometric read-out of compartmentalized signaling. SMO agonist pharmacological challenge tests reserve capacity. Critical weakness: ciliary signaling evidence base concerns Huntington's disease and neurodevelopmental disorders—not adult-onset ALS/AD. Mechanistic link from developmental ciliary defects to progressive adult neurodegeneration is unsubstantiated.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["FRET cAMP Sensor<br/>Targeting"]
B["ARL13B Ciliary<br/>Anchor"]
C["PSD95 Synaptic<br/>Compartment Anchor"]
D["Compartmentalized<br/>cAMP Signaling"]
E["ADCY3 Adenylate<br/>Cyclase Activity"]
F["GNAI1/GNAI3<br/>GPCR Signaling"]
G["Neuronal Polarity<br/>Quantitative Readout"]
A --> B
A --> C
B --> D
C --> D
E --> D
F --> D
D --> G
style A fill:#004d40,stroke:#80cbc4,color:#80cbc4
style G fill:#e65100,stroke:#ffab91,color:#ffab91⚖️ Evidence
⚖️ Evidence Matrix3 supports4 contradicts
Contradicts
Primary cilia primarily studied in dividing cells and specialized neurons; evidence thin for cortical/spinal motor neurons relevant to ALS/AD
Contradicts
Ciliopathies produce developmental phenotypes; adult-onset neurodegeneration involves distinct mechanisms—mechanistic link unsubstantiated
Contradicts
SMO agonist measures pathway responsiveness, not structural compartmentalization integrity
Contradicts
FRET sensor cross-talk and bleedthrough between compartments will produce artifactual ratiometric signals in single-axon imaging
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — ADCY3
No curated PDB or AlphaFold mapping for ADCY3 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for ADCY3 (adenylate cyclase), ARL13B (ciliary targeting), GNAI1/GNAI3 (GPCR signaling) 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 ADCY3 (adenylate cyclase), ARL13B (ciliary targeting), GNAI1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF human iPSC-derived cortical neurons from familial AD patients (PSEN1-M146V, APP Swe, or MAPT P301L mutations) are challenged with recombinant SHH ligand (400 ng/mL) THEN ciliary ARL13B-marked adeny | Blunted ciliary cAMP accumulation: peak FRET ratio change of 0.15 ± 0.05 ΔR/R in AD neurons vs. 0.35 ± 0.08 ΔR/R in corrected controls following SHH + forskolin | — no observation — | pending | 0.28 |
| IF adult SOD1-G93A ALS mice (90 days old) receive acute SMO agonist (SAG, 200 nM) challenge via intracerebroventricular injection THEN the ratiometric cAMP FRET signal ratio between ARL13B-targeted ci | Significant reduction in compartmentalized cAMP signaling reserve capacity,表现为ARL13B-ciliary/PSD95-synaptic FRET ratio drop from baseline 1.2 ± 0.1 to ≤0.84 ± 0 | — no observation — | pending | 0.35 |
🔮 Falsifiable Predictions (2)
pendingconf 35%
IF adult SOD1-G93A ALS mice (90 days old) receive acute SMO agonist (SAG, 200 nM) challenge via intracerebroventricular injection THEN the ratiometric cAMP FRET signal ratio between ARL13B-targeted ciliary and PSD95-targeted synaptic compartments will decrease by ≥30% compared to age-matched WT cont
Predicted outcome: Significant reduction in compartmentalized cAMP signaling reserve capacity,表现为ARL13B-ciliary/PSD95-synaptic FRET ratio drop from baseline 1.2 ± 0.1 to
Falsification: No significant difference in ciliary:synaptic cAMP FRET ratio between SOD1-G93A and WT mice (ratio remains within 1.1-1.3 range, p > 0.05 by unpaired t-test), indicating intact Shh reserve capacity in
pendingconf 28%
IF human iPSC-derived cortical neurons from familial AD patients (PSEN1-M146V, APP Swe, or MAPT P301L mutations) are challenged with recombinant SHH ligand (400 ng/mL) THEN ciliary ARL13B-marked adenylate cyclase activity will show ≥40% attenuation of forskolin-potentiated cAMP response compared to
Predicted outcome: Blunted ciliary cAMP accumulation: peak FRET ratio change of 0.15 ± 0.05 ΔR/R in AD neurons vs. 0.35 ± 0.08 ΔR/R in corrected controls following SHH +
Falsification: AD patient-derived neurons exhibit equivalent or greater ciliary cAMP responses to SHH + forskolin compared to corrected controls (ΔR/R ≥ 0.30, no significant difference by Mann-Whitney U test), dispr
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _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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