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.
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:#ffab91No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for ADCY3 yet. Search RCSB →
Median TPM across 13 brain regions for ADCY3 (adenylate cyclase), ARL13B (ciliary targeting), GNAI1/GNAI3 (GPCR signaling) from GTEx v10.
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.
| 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 |