VPS26/VPS29/VPS35 retromer complex maintains axonal endosomal signaling microdomains controlling TrkB/p75NTR trafficking. Impaired retromer causes somatodendritic receptor mislocalization disrupting synaptic plasticity. TrkB-mScarlet time-lapse imaging in microfluidic chambers provides compartmentalization index (somatic/axonal fluorescence ratio). CCN1 bicyclic peptide is proof-of-mechanism agonist but requires IND-enabling studies. VPS35 P294S variant increases AD risk; VPS35 mutations linked to late-onset PD.
Curated pathway from expert analysis
flowchart TD
A["VPS35-VPS26-VPS29<br/>Retromer Core Trimer"]
B["Endosomal Cargo Recognition<br/>CI-MPR/ATG9/SorLA Retrieval"]
C["Retrograde Trafficking<br/>Endosome-to-TGN"]
D["WASH Complex Recruitment<br/>Actin Branching on Endosome"]
E["Cathepsin D Maturation<br/>Lysosomal Hydrolase Sorted"]
F["VPS35 D620N Mutation<br/>Parkinson's PARK17"]
G["Lysosomal Dysfunction<br/>Alpha-Synuclein Accumulation"]
A --> B
B --> C
C --> D
C --> E
F -.->|"impairs"| A
F --> G
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#1b5e20,stroke:#81c784,color:#81c784
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for VPS35 yet. Search RCSB →
Median TPM across 13 brain regions for VPS35, VPS26, VPS29 (retromer complex); TrkB/NTRK2 (cargo receptors) 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 VPS35, VPS26, VPS29 (retromer complex); TrkB.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF VPS35 is knocked down in primary rat cortical neurons, THEN the axonal/somatic TrkB‑mScarlet fluorescence ratio will decrease by at least 30% within 48 h after transfection. | Axonal/somatic TrkB‑mScarlet fluorescence ratio reduced by ≥30% relative to scrambled‑siRNA control. | — no observation — | pending | 0.75 |
| IF CCN1 bicyclic peptide (10 mg/kg, i.p., daily) is administered to VPS35 P294S knock‑in mice for 4 weeks, THEN their Morris water maze escape latency will improve, reflected by a ≥20% reduction in la | Morris water maze escape latency reduced by ≥20% in CCN1‑treated versus vehicle‑treated VPS35 P294S mice. | — no observation — | pending | 0.70 |