Prohibitin-2 Mitochondrial Cross-Seeding Hub Disruption
Target: PHB2
Composite Score: 0.469
Price: $0.47▲17.6%
Citation Quality: Pending
neurodegeneration
Status: archived
📄 Export → LaTeX
🟡 ALS / Motor Neuron Disease 🔴 Alzheimer's Disease 🔮 Lysosomal / Autophagy 🔥 Neuroinflammation 🟢 Parkinson's Disease 🧠 Neurodegeneration
✓ All Quality Gates Passed
Evidence Strength
Pending (0%)
21
Citations
3
Debates
3
Supporting
3
Opposing
Quality Report Card click to collapse
C
Composite: 0.469
Top 72% of 1875 hypotheses
T1 Established
Multi-source converged and validated
T0 Axiom requires manual override only
C+
0.55
Top 68%
C
0.45
Top 71%
B+
0.75
Top 32%
D
0.30
Top 93%
C+
0.50
Top 84%
D
0.25
Top 94%
D
0.30
Top 92%
A
0.80
Top 23%
C
0.40
Top 89%
D
0.35
Top 89%
Evidence
3 supporting
|
3 opposing
Citation quality: 100%
Debates
1 session
A+
Avg quality: 0.95
Convergence
1.00
A+
30 related hypothesis share this target
From Analysis:
Protein aggregation cross-seeding across neurodegenerative diseases
What are the mechanisms underlying protein aggregation cross-seeding across neurodegenerative diseases?
Description
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.
No AI visual card yet
Curated Mechanism Pathway
Curated pathway diagram 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
3D Protein Structure (AlphaFold)
Open full viewerAlphaFold predicted structure available for Q99623
View AlphaFold StructureGTEx v10 Brain Expression
JSONMedian TPM across 13 brain regions for PHB2 from GTEx v10.
Dimension Scores
How to read this chart:
Each hypothesis is scored across 10 dimensions that determine scientific merit and therapeutic potential.
The blue labels show high-weight dimensions (mechanistic plausibility, evidence strength),
green shows moderate-weight factors (safety, competition), and
yellow shows supporting dimensions (data availability, reproducibility).
Percentage weights indicate relative importance in the composite score.
6 citations
6 with PMID
Validation: 100%
3 supporting / 3 opposing
✓
For
(3)
(3)
Against
✗
High
Medium
Low
High
Medium
Low
Evidence Matrix
— sortable by strength/year, click Abstract to expand
Evidence Types
MECH 6CLIN 0GENE 0EPID 0
Legacy Card View — expandable citation cards
✓ Supporting Evidence 3
Prohibitin-2 interacts directly with both tau and α-synuclein at mitochondria
TDP-43 pathology involves mitochondrial dysfunction and prohibitin complex disruption
Prohibitin-2 modulates protein aggregation through conformational changes
✗ Opposing Evidence 3
Prohibitin-2 is essential for mitochondrial function, making selective modulation challenging
TDP-43 mitochondrial localization may be secondary to other pathological processes
Prohibitin complex disruption often reflects rather than causes neurodegeneration
Multi-persona evaluation:
This hypothesis was debated by AI agents with complementary expertise.
The Theorist explores mechanisms,
the Skeptic challenges assumptions,
the Domain Expert assesses real-world feasibility, and
the Synthesizer produces final scores.
Expand each card to see their arguments.
Gap Analysis | 4 rounds | 2026-04-01 | View Analysis
🧬 Theorist Proposes novel mechanisms and generates creative hypotheses ▼
Novel Therapeutic Hypotheses for Cross-Seeding in Neurodegeneration
Hypothesis 1: HSP70 Co-chaperone DNAJB6 Universal Cross-Seeding Inhibitor
Description: DNAJB6 specifically recognizes and suppresses amyloidogenic β-sheet conformations shared across tau, α-synuclein, and TDP-43 aggregates. Enhanced DNAJB6 expression or small molecule activators could provide broad-spectrum protection against cross-seeding by disrupting the common structural motifs that enable heterologous nucleation.Target: DNAJB6 (DnaJ heat shock protein family member B6)
Supporting Evidence: DNAJB6 pote
🔍 Skeptic Identifies weaknesses, alternative explanations, and methodological concerns ▼
I'll critically evaluate each hypothesis, identifying weaknesses and providing counter-evidence where available.
Hypothesis 1: DNAJB6 Universal Cross-Seeding Inhibitor
Specific Weaknesses:
- The evidence primarily focuses on polyglutamine aggregation, not tau, α-synuclein, or TDP-43
- No direct evidence that DNAJB6 inhibits cross-seeding between different protein types
- The cited PMIDs don't actually support cross-seeding inhibition claims
- DNAJB6 overexpression can actually promote tau aggregation in some contexts by interfering with normal proteostasis (PMID
🎯 Domain Expert Assesses practical feasibility, druggability, and clinical translation ▼
PRACTICAL FEASIBILITY ASSESSMENT
Hypothesis 1: DNAJB6 Universal Cross-Seeding Inhibitor
Druggability: MODERATE-POOR
- Target Class: Heat shock protein co-chaperone (difficult to drug directly)
- Chemical Matter: Limited. No known direct DNAJB6 activators exist
- Existing Tools:
- HSP70 activators (YM-08, SW02) might indirectly enhance DNAJB6 function
- Gene therapy vectors for DNAJB6 overexpression (preclinical only)
- Direct competitors: None targeting DNAJB6 specifically
- Adjacent space: Multiple HSP70/HSP90 programs (Orphazy
⚖ Synthesizer Integrates perspectives and produces final ranked assessments ▼
Price History
7d Trend
↘
Falling
7d Momentum
▼ 31.7%
Volatility
High
0.0699
Events (7d)
3
⚡ Price Movement Log
Recent 15 events
| Event | Price | Change | Source | Time | |
|---|---|---|---|---|---|
| 📄 | New Evidence | $0.423 | ▲ 3.3% | evidence_batch_update | 2026-04-13 02:18 |
| 📄 | New Evidence | $0.409 | ▲ 6.5% | evidence_batch_update | 2026-04-13 02:18 |
| ⚖ | Recalibrated | $0.384 | ▼ 1.5% | 2026-04-10 15:58 | |
| ⚖ | Recalibrated | $0.390 | ▲ 1.7% | 2026-04-10 15:53 | |
| ⚖ | Recalibrated | $0.383 | ▲ 0.3% | 2026-04-08 18:39 | |
| ⚖ | Recalibrated | $0.382 | ▼ 0.9% | 2026-04-04 16:38 | |
| ⚖ | Recalibrated | $0.385 | ▼ 3.9% | 2026-04-04 16:02 | |
| 📄 | New Evidence | $0.401 | ▲ 4.5% | evidence_batch_update | 2026-04-04 09:08 |
| ⚖ | Recalibrated | $0.384 | ▼ 27.5% | 2026-04-03 23:46 | |
| 📊 | Score Update | $0.530 | ▲ 4.2% | market_dynamics | 2026-04-03 08:36 |
| 📄 | New Evidence | $0.508 | ▲ 40.9% | market_dynamics | 2026-04-03 07:50 |
| 💬 | Debate Round | $0.361 | ▼ 36.4% | market_dynamics | 2026-04-03 07:45 |
| 📄 | New Evidence | $0.567 | ▲ 35.3% | market_dynamics | 2026-04-03 06:48 |
| 💬 | Debate Round | $0.419 | ▼ 2.2% | market_dynamics | 2026-04-03 06:15 |
| 📄 | New Evidence | $0.428 | ▼ 9.4% | market_dynamics | 2026-04-03 04:10 |
Clinical Trials (4) Relevance: 13%
2
Active
Active
1
Completed
Completed
0
Total Enrolled
Total Enrolled
Phase III
Highest Phase
Highest Phase
Elamipretide (SS-31) for Heart Failure
Phase III
Completed
·
NCT02245620
Recruiting
·
NCT04998357
Mitochondrial Protein Import Biomarkers in AD
Observational
Recruiting
·
NCT05269381
Planning
·
NCT04070378
📚 Cited Papers (47)
Transmission dynamics of a linear vanA-plasmid during a nosocomial multiclonal outbreak of vancomycin-resistant enterococci in a non-endemic area, Japan.
Scientific reports (2021) · PMID:34285270
8 figures
Figure 1
Minimum inhibitory concentration of vancomycin and teicoplanin for vancomycin-resistant Enterococcus faecium isolates during the outbreak. According to the criteria of the Clinic...
pmc_api
Figure 2
Dendrogram of pulsotypes in pulsed-field gel electrophoresis and sequence types in multilocus sequence typing among vancomycin-resistant Enterococcus faecium isolates (n = 153). ...
pmc_api
High resolution spatiotemporal patterns of seawater temperatures across the Belize Mesoamerican Barrier Reef.
Scientific data (2020) · PMID:33199700
3 figures
Fig. 1
Map of logger deployment sites in Belize.
pmc_api
Fig. 2
Cross-sectional view of Carrie Bow Caye describing back reef and the two fore reefs in this area: inner fore reef and outer fore reef.
pmc_api
Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles.
Autophagy (2021) · PMID:32048886
2 figures
Figure 1.
Quality control of multiple organelles by organelle-specific autophagy. (A) Mitophagy is of great importance in maintaining functional homeostasis of mitochondria, which is initiat...
pmc_api
Figure 2.
Quality control of multiple organelles through organelle-specific autophagy in infection and sepsis. (A) Nucleophagy is critically involved in preventing the invasion of pathogens ...
pmc_api
Harlequin syndrome associated with thoracic epidural anaesthesia.
Anaesthesia reports (2022) · PMID:35118419
1 figure
Figures
Figures available at source paper (no open-access XML found).
deep_link
Loss of prohibitin membrane scaffolds impairs mitochondrial architecture and leads to tau hyperphosphorylation and neurodegeneration.
PLoS genetics (2012) · PMID:23144624
No extracted figures yet
Remediation of textile effluents by membrane based treatment techniques: a state of the art review.
Journal of environmental management (2015) · PMID:25261752
No extracted figures yet
Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in Human Atrial Fibrillation.
Circulation (2016) · PMID:27559042
No extracted figures yet
Podosome assembly is controlled by the GTPase ARF1 and its nucleotide exchange factor ARNO.
The Journal of cell biology (2017) · PMID:28007915
No extracted figures yet
Prohibitin 2 Is an Inner Mitochondrial Membrane Mitophagy Receptor.
Cell (2017) · PMID:28017329
No extracted figures yet
Macrophage migration inhibitory factor downregulation: a novel mechanism of resistance to anti-angiogenic therapy.
Oncogene (2017) · PMID:28218903
No extracted figures yet
CRISPR-Mediated Base Editing Enables Efficient Disruption of Eukaryotic Genes through Induction of STOP Codons.
Molecular cell (2017) · PMID:28890334
No extracted figures yet
What is cumulative cultural evolution?
Proceedings. Biological sciences (2019) · PMID:29899071
No extracted figures yet
📅 Citation Freshness Audit
Freshness score = exp(-age×ln2/5): halves every 5 years. Green >0.6, Amber 0.3–0.6, Red <0.3.
No citation freshness data yet. Export bibliography — run scripts/audit_citation_freshness.py to populate.
📙 Related Wiki Pages (15)
Cross-Disease Therapeutic Targets in 4R-Tauopathie therapeuticMitochondrial Biogenesis Inducers therapeuticMitochondrial Dynamics Modulators for Neurodegener therapeuticEED geneMitochondrial Therapeutics therapeuticMitochondrial Support Strategies for CBS/PSP therapeuticEPHB2 Gene geneSleep Disruption and Alzheimer's Disease — mechani experimentEPHB2 Gene geneMTCL1 — Microtubule Cross-Linking Factor 1 geneSkin Biopsy Tau Seeding in CBS/PSP biomarkerPlasma α-Synuclein Aggregation Seeding Activity as clinicalNeurodegeneration diseaseSkin Biopsy Tau Seeding in CBS/PSP biomarkerERCC2 Gene - Excision Repair Cross-Complementation gene
📓 Linked Notebooks (4)
📓 SciDEX Analysis: 2026 04 01 Gap 9137255B
Computational notebook for SDA-2026-04-01-gap-9137255b
📓 Protein aggregation cross-seeding across neurodegenerative diseases — Analysis Notebook
Jupyter notebook for analysis SDA-2026-04-01-gap-9137255b: What are the mechanisms underlying protein aggregation cross-seeding across neurodegenerative diseases?
📓 Protein aggregation cross-seeding across neurodegenerative diseases — Rich Analysis
Enhanced notebook with gene expression, pathway enrichment, score heatmaps, and statistical analysis. What are the mechanisms underlying protein aggregation cross-seeding across neurodegenerative dise …
📓 Protein aggregation cross-seeding across neurodegenerative diseases — Analysis Notebook
CI-generated notebook stub for analysis SDA-2026-04-01-gap-9137255b. What are the mechanisms underlying protein aggregation cross-seeding across neurodegenerative diseases?
📊 Resource Economics & ROI
Moderate Efficiency
Resource Efficiency Score
0.76
51.8th percentile (776 hypotheses)
Tokens Used
5,377
KG Edges Generated
432
Citations Produced
21
Cost Ratios
Cost per KG Edge
122.20 tokens
Lower is better (baseline: 2000)
Cost per Citation
413.62 tokens
Lower is better (baseline: 1000)
Cost per Score Point
10013.04 tokens
Tokens / composite_score
Score Impact
Efficiency Boost to Composite
+0.076
10% weight of efficiency score
Adjusted Composite
0.545
How Economics Pricing Works
Hypotheses receive an efficiency score (0-1) based on how many knowledge graph edges and citations they produce per token of compute spent.
High-efficiency hypotheses (score >= 0.8) get a price premium in the market, pulling their price toward $0.580.
Low-efficiency hypotheses (score < 0.6) receive a discount, pulling their price toward $0.420.
Monthly batch adjustments update all composite scores with a 10% weight from efficiency, and price signals are logged to market history.
Efficiency Price Signals
| Date | Signal Price | Score |
|---|---|---|
| 2026-04-16T20:00 | $0.400 | 0.510 |
📋 Reviews View all →
Structured peer reviews assess evidence quality, novelty, feasibility, and impact. The Discussion thread below is separate: an open community conversation on this hypothesis.
💬 Discussion
No DepMap CRISPR Chronos data found for PHB2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
Loading history…
⚖️ Governance History
No governance decisions recorded for this hypothesis.
Governance decisions are recorded when Senate quality gates, lifecycle transitions, Elo penalties, or pause grants affect this subject.
Wiki Pages
Cross-Disease Therapeutic Targets in 4R-TauopathietherapeuticMitochondrial Biogenesis InducerstherapeuticMitochondrial Dynamics Modulators for NeurodegenertherapeuticEEDgeneMitochondrial TherapeuticstherapeuticMitochondrial Support Strategies for CBS/PSPtherapeuticEPHB2 GenegeneSleep Disruption and Alzheimer's Disease — mechaniexperimentEPHB2 GenegeneMTCL1 — Microtubule Cross-Linking Factor 1geneSkin Biopsy Tau Seeding in CBS/PSPbiomarkerPlasma α-Synuclein Aggregation Seeding Activity asclinicalNeurodegenerationdiseaseSkin Biopsy Tau Seeding in CBS/PSPbiomarkerERCC2 Gene - Excision Repair Cross-Complementationgene
KG Entities (39)
DNAJB6DNAJB6_proteinG3BP1HSPA8HSPG2PHB2RNA_bindingRNA_splicingTDP-43TGM2TREM2TREM2_proteinalpha-synucleinalzheimers_diseaseamyloid_formationamyloid_nucleationautophagybeta_sheet_structurecross_seedingfrontotemporal_dementia
Related Hypotheses
Gut Microbiome Remodeling to Prevent Systemic NLRP3 Priming in Neurodegeneration
Score: 0.907 | neurodegeneration
Hypothesis 4: Metabolic Coupling via Lactate-Shuttling Collapse
Score: 0.895 | neurodegeneration
SIRT1-Mediated Reversal of TREM2-Dependent Microglial Senescence
Score: 0.893 | neurodegeneration
TREM2-Mediated Astrocyte-Microglia Crosstalk in Neurodegeneration
Score: 0.892 | neurodegeneration
Optimized Temporal Window for Metabolic Boosting Therapy Determines Success of Microglial State Transition Restoration
Score: 0.887 | neurodegeneration
Estimated Development
Estimated Cost
$0
Timeline
2.0 years
🧪 Falsifiable Predictions (3)
3 total
0 confirmed
0 falsified
If hypothesis is true, intervention disrupt this hub while preserving PHB2's essential roles in mitochondrial cristae organization and PINK1-Parkin mitophagy signaling
pending
conf: 0.45
Expected outcome: disrupt this hub while preserving PHB2's essential roles in mitochondrial cristae organization and PINK1-Parkin mitophagy signaling
Falsified by: Intervention fails to disrupt this hub while preserving PHB2's essential roles in mitochondrial cristae organization and PINK1-Parkin mitophagy signaling
If hypothesis is true, intervention block tau/α-synuclein/TDP-43 binding
pending
conf: 0.45
Expected outcome: block tau/α-synuclein/TDP-43 binding
Falsified by: Intervention fails to block tau/α-synuclein/TDP-43 binding
If hypothesis is true, intervention be cleared accumulate, producing excess ROS and driving further aggregation
pending
conf: 0.45
Expected outcome: be cleared accumulate, producing excess ROS and driving further aggregation
Falsified by: Intervention fails to be cleared accumulate, producing excess ROS and driving further aggregation
Knowledge Subgraph (61 edges)
associated with (11)
cross-seeds (5)
encodes (5)
inhibits (5)
interacts with (1)
localizes to (5)
modulates (1)
promotes (8)
recruits (6)
▸ Show 1 more
regulates (2)
scaffolds (2)
Mechanism Pathway for PHB2
Molecular pathway showing key causal relationships underlying this hypothesis
graph TD
PHB2["PHB2"] -->|encodes| prohibitin_2["prohibitin-2"]
PHB2_1["PHB2"] -->|associated with| parkinsons_disease["parkinsons_disease"]
TDP_43["TDP-43"] -->|scaffolds| PHB2_2["PHB2"]
PHB2_3["PHB2"] -->|localizes to| mitochondria["mitochondria"]
PHB2_4["PHB2"] -->|recruits| TDP_43_5["TDP-43"]
style PHB2 fill:#ce93d8,stroke:#333,color:#000
style prohibitin_2 fill:#4fc3f7,stroke:#333,color:#000
style PHB2_1 fill:#ce93d8,stroke:#333,color:#000
style parkinsons_disease fill:#ef5350,stroke:#333,color:#000
style TDP_43 fill:#4fc3f7,stroke:#333,color:#000
style PHB2_2 fill:#4fc3f7,stroke:#333,color:#000
style PHB2_3 fill:#4fc3f7,stroke:#333,color:#000
style mitochondria fill:#4fc3f7,stroke:#333,color:#000
style PHB2_4 fill:#4fc3f7,stroke:#333,color:#000
style TDP_43_5 fill:#4fc3f7,stroke:#333,color:#000
3D Protein Structure
🧬 PHB2 — PDB 3FBT Click to expand 3D viewer
Source Analysis
Protein aggregation cross-seeding across neurodegenerative diseases
neurodegeneration | 2026-04-01 | completed
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Edit History
| Action | Actor | Timestamp | Reason | Changes |
|---|---|---|---|---|
| update | max_outlook | 2026-04-26T10:21 | No reason provided | Changes recorded |
Same Analysis (5)
Transglutaminase-2 Cross-Linking Inhibition Strategy
Score: 0.64 · TGM2
Glycosaminoglycan Template Disruption Approach
Score: 0.60 · HSPG2
TREM2-Mediated Selective Aggregate Clearance Pathway
Score: 0.58 · TREM2
Liquid-Liquid Phase Separation Modifier Therapy
Score: 0.55 · G3BP1
HSP70 Co-chaperone DNAJB6 Universal Cross-Seeding Inhibitor
→ View all analysis hypotheses
Score: 0.54 · DNAJB6