VPS35 Retromer Restoration to Rescue Endosomal Protein Trafficking
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/VPS35 complex) 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.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF VPS35 protein levels are restored to ≥80% of wild-type levels in VPS35-knockdown SH-SY5Y neuronal cells via CRISPR-activation, THEN the surface expression of the retromer cargo protein SorLA will i | SorLA surface expression will increase by ≥2-fold, quantified by cell-surface biotinylation assay and flow cytometry. | — no observation — | pending | 0.60 |
| IF VPS35 expression is restored via viral transduction (AAV-VPS35) in VPS35-deficient patient-derived fibroblasts, THEN the rate of transferrin receptor recycling will increase by at least 40% compare | Transferrin receptor recycling rate will increase by ≥40% relative to baseline deficiency, measured by live-cell imaging of fluorescent transferrin. | — no observation — | pending | 0.65 |