ID: h-1e2b7f1c
Hypothesis
VPS35 Retromer Restoration to Rescue Endosomal Protein Trafficking
VPS35 Retromer Restoration to Rescue Endosomal Protein Trafficking.
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 5 support✗ 6 oppose
🧪 Overview
VPS35 Retromer Restoration to Rescue Endosomal Protein Trafficking
🧬 Mechanism
🧬 Curated Mechanism Pathway
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:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix5 supports6 contradicts
Supports
VPS35 mutations cause autosomal-dominant Parkinson's disease with synaptic dysfunction
Supports
Retromer protein levels are reduced in AD hippocampus and correlate with cognitive decline
Supports
Retromer dysfunction causes APP mislocalization to endosomes, increasing Aβ production
Supports
R55 compound rescues VPS35 mutations and restores retromer function in cellular models
Supports
Retromer mediates retrieval of synaptic receptors (APP, Vps10, SorLA) from degradative pathway
Contradicts
Retromer enhancement increases Aβ production in some cellular models by redirecting APP to amyloidogenic compartments
Contradicts
R55 compound validation limited to HeLa cells and yeast; no human neuron data
Contradicts
Retromer affects thousands of cargo including Wntless, glutamate receptors, transferrin receptor
Contradicts
Correlation between VPS35 levels and cognitive decline may be secondary to neurodegeneration
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — VPS35
No curated PDB or AlphaFold mapping for VPS35 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for VPS35 (VPS26/VPS29/VPS35 complex) 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 VPS35 (VPS26.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
Cost
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Timeline
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🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
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Stable
7d Momentum
▲ 0.0%
Volatility
Low
0.0145
Events (7d)
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Price History
▲4.5%💾 Resource Usage
LLM Tokens
39,448
$0.1183
Total Cost
$0.1183
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| 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 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
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% compared to non-transduced VPS35-deficient cells within 72 hours post-transduction.
Predicted outcome: Transferrin receptor recycling rate will increase by ≥40% relative to baseline deficiency, measured by live-cell imaging of fluorescent transferrin.
Falsification: Transferrin receptor recycling rate remains below 20% of wild-type levels, or endosomal cargo mislocalization persists (≥80% of cells showing cytoplasmic aggregation of retromer cargo proteins CI-M6PR
pendingconf 60%
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 increase by at least 2-fold compared to non-activated knockdown cells within 48 hours.
Predicted outcome: SorLA surface expression will increase by ≥2-fold, quantified by cell-surface biotinylation assay and flow cytometry.
Falsification: SorLA surface expression shows no statistically significant increase (p>0.05, n=4 replicates), or total cellular SorLA levels remain ≥50% below wild-type controls indicating trafficking block persists
▸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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