Prohibitin-2 serves as a convergent mitochondrial platform where tau, α-synuclein, and TDP-43 interact and undergo conformational templating. Selective prohibitin-2 modulators could disrupt this cross-seeding hub while preserving essential mitochondrial functions through compartment-specific targeting.
Curated pathway from expert analysis
graph TD
A["PHB2 on Mitochondrial Inner Membrane"] --> B["Scaffolding/Structural Role"]
B --> C["Cristae Organization"]
B --> D["Mitophagy Receptor Function"]
E["Tau"] --> F["Binds PHB2 on Mito Surface"]
G["alpha-Synuclein"] --> F
H["TDP-43"] --> F
F --> I["PHB2 as Convergent Cross-Seeding Hub"]
I --> J["Conformational Templating"]
J --> K["Heterologous Protein Aggregation"]
K --> L["Multi-Protein Toxic Complexes"]
L --> M["Mitochondrial Membrane Disruption"]
M --> N["Bioenergetic Collapse"]
N --> O["Neurodegeneration"]
P["PHB2 Modulator Therapy"] --> Q["Disrupt PHB2-Aggregate Interaction"]
Q --> R["Block Cross-Seeding Platform"]
R --> S["Prevent Multi-Protein Aggregation"]
Q --> T["Preserve PHB2 Scaffolding Function"]
T --> U["Maintained Cristae Integrity"]
S --> V["Neuroprotection"]
U --> V
style A fill:#264653,stroke:#ffd54f,color:#e0e0e0
style I fill:#3a1a1a,stroke:#ef9a9a,color:#e0e0e0
style P fill:#1a3a4a,stroke:#4fc3f7,color:#e0e0e0
style V fill:#2a3a1a,stroke:#c5e1a5,color:#e0e0e0





No curated PDB or AlphaFold mapping for PHB2 yet. Search RCSB →
Median TPM across 13 brain regions for PHB2 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 PHB2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| If hypothesis is true, intervention disrupt this hub while preserving PHB2's essential roles in mitochondrial cristae organization and PINK1-Parkin mitophagy signaling | disrupt this hub while preserving PHB2's essential roles in mitochondrial cristae organization and PINK1-Parkin mitophagy signaling | — no observation — | pending | 0.45 |
| If hypothesis is true, intervention block tau/α-synuclein/TDP-43 binding | block tau/α-synuclein/TDP-43 binding | — no observation — | pending | 0.45 |
| If hypothesis is true, intervention be cleared accumulate, producing excess ROS and driving further aggregation | be cleared accumulate, producing excess ROS and driving further aggregation | — no observation — | pending | 0.45 |