Synaptic activity-dependent phosphorylation of synapsin-1 by CamKII and calcineurin dynamically regulates vesicle mobilization, while Cdk5-mediated phosphorylation of synaptophysin and SV2A facilitates interaction with APP in presynaptic terminals, creating a hub where impaired neurotransmitter release converges with local Aβ secretion.
Curated pathway from expert analysis
flowchart TD
A["Synaptic Activity<br/>Calcium Influx at Active Zone"]
B["CamKII Activation<br/>Synapsin-1 SYN1 Phosphorylation"]
C["SYN1 Dissociates from Reserve Pool<br/>Vesicle Mobilization"]
D["Calcineurin Dephosphorylation<br/>Feedback Vesicle Reclustering"]
E["Cdk5 Aberrant Activation<br/>SYN1 SV2A Synaptophysin Phosphorylation"]
F["Release Probability Reprogrammed<br/>Short-Term Plasticity Disrupted"]
G["APP Processing Modulated<br/>Secretase Access Altered by Vesicle State"]
H["Synaptic Dysfunction<br/>AD ALS Co-pathology"]
A --> B
B --> C
C --> D
D --> B
E --> F
F --> G
E --> H
G --> H
style E fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for SYN1 yet. Search RCSB →
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 SYN1 (Synapsin-1).
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we pharmacologically inhibit Cdk5 activity (using roscovitine) in primary hippocampal neurons AND simultaneously measure synaptic vesicle release probability (via FM4-64 destaining assays) and extr | Cdk5 inhibition will reduce extracellular Aβ42 concentration by ≥40% while release probability remains within ±15% of baseline, demonstrating dissociable effect | — no observation — | pending | 0.75 |
| IF we express synapsin-1 S9A phospho-mutant (non-phosphorylatable) in synapsin-1/2 double knockout neurons via viral transduction AND compare to wild-type synapsin-1 rescue, THEN the phospho-mutant wi | S9A-expressing neurons will show ≥50% reduction in synaptic vesicle mobilization (measured as refractory pool replenishment rate) and ≥40% reduction in synaptop | — no observation — | pending | 0.68 |