Neurons express a distinct V-ATPase subunit isoform profile (ATP6V0C splice variants and ATP6V1G2 enrichment) resulting in slower lysosomal acidification kinetics and defective lysosomal transport along microtubules. This creates a bottleneck where fusion-competent autophanosomes cannot efficiently intersect with properly acidified lysosomes, misinterpreted as 'autophagy resistance'. This hypothesis survived SKEPTIC critique with intact mechanistic specificity and was prioritized by DOMAIN_EXPERT as warranting prioritized investigation with distinct clinical development pathways.
Curated pathway from expert analysis
flowchart TD
A["Neuron-Specific V-ATPase Subunits<br/>ATP6V0 and ATP6V1 Composition"]
B["Slow Lysosomal Acidification<br/>Proton Pump Kinetics Reduced"]
C["ARL8B-SYX17 Trafficking Bottleneck<br/>Fusion-Competent Organelle Mismatch"]
D["Late Autophagy Stall<br/>Cargo Clearance Delayed"]
E["Proteostasis Stress<br/>Damaged Cargo Persistence"]
F["Neuronal Vulnerability<br/>Apparent Autophagy Resistance"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for ATP6V0 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 ATP6V0.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF ARL8B is genetically knocked down or SYX17 function is inhibited in primary mouse hippocampal neurons, THEN lysosomal transport velocity (anterograde and retrograde) along MAP2-positive dendrites w | Lysosomal transport velocity will decrease from baseline (∼0.5-0.8 μm/sec in dendrites) to ≤0.35 μm/sec, with ≥50% reduction in processive movements (defined as | — no observation — | pending | 0.55 |
| IF neuronal ATP6V0C splice variant expression or ATP6V1G2 levels are genetically reduced (knockdown via shRNA or CRISPRi) in human iPSC-derived neurons, THEN lysosomal acidification rate (measured by | Lysosomal acidification rate will increase by ≥40% (faster pH drop from baseline to pH 4.5) and steady-state lysosomal pH will decrease by ≥0.3 units compared t | — no observation — | pending | 0.45 |