Genetically modified microglia overexpressing mitochondrial export machinery package healthy mitochondria into extracellular vesicles with neuron-specific targeting ligands.
Curated pathway from expert analysis
graph TD
A["Microglia"] --> B["Natural EV Secretion"]
B --> C["Extracellular Vesicles"]
D["Engineering EVs"] --> E["RAB27A Overexpression"]
E --> F["Enhanced EV Production"]
D --> G["LAMP2B Surface Targeting"]
G --> H["Neuron-Specific Ligands"]
H --> I["Targeted EV Delivery"]
D --> J["Load Healthy Mitochondria"]
J --> K["Mito-Enriched EVs"]
F --> L["Engineered Microglia-EVs"]
I --> L
K --> L
L --> M["Targeted Delivery to Damaged Neurons"]
N["Damaged Neurons"] --> O["Mitochondrial Dysfunction"]
O --> P["Energy Failure"]
M --> Q["Mito Integration into Neurons"]
Q --> R["Restored Bioenergetics"]
R --> S["Neuronal Rescue"]
T["Advantages"] --> U["Cross BBB via EVs"]
T --> V["Cell-Type-Specific Targeting"]
T --> W["Scalable Production"]
S --> X["Targeted Mitochondrial Therapy"]
style A fill:#264653,stroke:#ffd54f,color:#e0e0e0
style D fill:#1a3a4a,stroke:#4fc3f7,color:#e0e0e0
style M fill:#1a3a2a,stroke:#81c784,color:#e0e0e0
style X fill:#2a3a1a,stroke:#c5e1a5,color:#e0e0e0

No curated PDB or AlphaFold mapping for RAB27A yet. Search RCSB →
Median TPM across 13 brain regions for RAB27A/LAMP2B from GTEx v10.
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 RAB27A.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| If hypothesis is true, intervention be assessed using MitoTracker dyes and electron microscopy of isolated EVs | be assessed using MitoTracker dyes and electron microscopy of isolated EVs | — no observation — | pending | 0.30 |
| If hypothesis is true, intervention involve primary microglia or immortalized microglial cell lines (BV2, N9) transfected with lentiviral vectors expressing RAB27A and LAMP2B-RVG fusion proteins | involve primary microglia or immortalized microglial cell lines (BV2, N9) transfected with lentiviral vectors expressing RAB27A and LAMP2B-RVG fusion proteins | — no observation — | pending | 0.30 |
| If hypothesis is true, intervention restore neuronal bioenergetics in neurodegenerative conditions | restore neuronal bioenergetics in neurodegenerative conditions | — no observation — | pending | 0.30 |
| If hypothesis is true, intervention rescue bioenergetic deficits in Parkinson's disease models | rescue bioenergetic deficits in Parkinson's disease models | — no observation — | pending | 0.30 |