HSP70 Co-chaperone DNAJB6 Universal Cross-Seeding Inhibitor
Target: DNAJB6
Composite Score: 0.544
Price: $0.54▲54.2%
Citation Quality: Pending
neurodegeneration
Status: proposed
🟢 Parkinson's Disease 🔮 Lysosomal / Autophagy 🔥 Neuroinflammation 🔴 Alzheimer's Disease 🟡 ALS / Motor Neuron Disease 🧠 Neurodegeneration
✓ All Quality Gates Passed
Quality Report Card click to collapse
C+
Composite: 0.544
Top 66% of 1374 hypotheses
T5 Contested
Contradicted by evidence, under dispute
B
0.65
Top 49%
C
0.45
Top 76%
A
0.80
Top 25%
C
0.45
Top 71%
B
0.60
Top 62%
D
0.35
Top 84%
C
0.40
Top 80%
A
0.80
Top 22%
C+
0.50
Top 68%
C+
0.55
Top 58%
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?
Hypotheses from Same Analysis (6)
These hypotheses emerged from the same multi-agent debate that produced this hypothesis.
Transglutaminase-2 Cross-Linking Inhibition Strategy
Score: 0.639 | Target: TGM2
Glycosaminoglycan Template Disruption Approach
Score: 0.597 | Target: HSPG2
TREM2-Mediated Selective Aggregate Clearance Pathway
Score: 0.584 | Target: TREM2
Liquid-Liquid Phase Separation Modifier Therapy
Score: 0.551 | Target: G3BP1
Prohibitin-2 Mitochondrial Cross-Seeding Hub Disruption
Score: 0.469 | Target: PHB2
RNA-Binding Competition Therapy for TDP-43 Cross-Seeding
Score: 0.465 | Target: TARDBP
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.
No AI visual card yet
Curated Mechanism Pathway
Curated pathway diagram from expert analysis
graph TD
A["Misfolded Protein Seeds"] --> B["alpha-Synuclein Aggregation"]
A --> C["Tau Fibrillization"]
A --> D["TDP-43 Inclusion Formation"]
B --> E["Cross-Seeding Between Proteins"]
C --> E
D --> E
E --> F["Amplified Aggregate Toxicity"]
F --> G["Neurodegeneration Spread"]
H["DNAJB6 Co-chaperone"] --> I["J-Domain Binds HSP70"]
I --> J["HSP70 ATPase Activation"]
J --> K["Substrate Recognition"]
K --> L["Bind Amyloid Nuclei"]
L --> M["Block Fibril Elongation"]
L --> N["Prevent Cross-Seeding"]
O["DNAJB6 Upregulation Therapy"] --> P["Enhanced DNAJB6 Expression"]
P --> Q["Increased HSP70 Recruitment"]
Q --> R["Universal Anti-Aggregation"]
R --> S["Inhibit alpha-Syn Fibrillization"]
R --> T["Inhibit Tau Aggregation"]
R --> U["Inhibit TDP-43 Inclusions"]
S --> V["Pan-Neurodegenerative Protection"]
T --> V
U --> V
style A fill:#4a1942,stroke:#ce93d8,color:#e0e0e0
style H fill:#1a3a4a,stroke:#4fc3f7,color:#e0e0e0
style R fill:#1a3a2a,stroke:#81c784,color:#e0e0e0
style V fill:#2a3a1a,stroke:#c5e1a5,color:#e0e0e0
3D Protein Structure (AlphaFold)
Open full viewerAlphaFold predicted structure available for O75190
View AlphaFold StructureDimension 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 4CLIN 0GENE 2EPID 0
Legacy Card View — expandable citation cards
✓ Supporting Evidence 3
DNAJB6 potently inhibits polyglutamine aggregation and maintains soluble protein conformations
HSP70 co-chaperones show specificity for misfolded β-sheet structures across different amyloidogenic proteins
DNAJB6 variants are associated with reduced risk of multiple neurodegenerative diseases
✗ Opposing Evidence 3
DNAJB6 overexpression can actually promote tau aggregation in some contexts by interfering with normal proteos…▼
DNAJB6 overexpression can actually promote tau aggregation in some contexts by interfering with normal proteostasis
HSP70 co-chaperones show substrate specificity that may not translate across different amyloidogenic proteins
DNAJB6 mutations cause myopathy through gain-of-function mechanisms, suggesting enhanced activity may be harmf…▼
DNAJB6 mutations cause myopathy through gain-of-function mechanisms, suggesting enhanced activity may be harmful
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
↔
Stable
7d Momentum
▼ 0.8%
Volatility
Low
0.0145
Events (7d)
6
⚡ Price Movement Log
Recent 15 events
| Event | Price | Change | Source | Time | |
|---|---|---|---|---|---|
| ⚖ | Recalibrated | $0.420 | ▼ 1.3% | 2026-04-10 15:58 | |
| ⚖ | Recalibrated | $0.426 | ▲ 1.6% | 2026-04-10 15:53 | |
| ⚖ | Recalibrated | $0.419 | ▲ 0.3% | 2026-04-08 18:39 | |
| ⚖ | Recalibrated | $0.418 | ▼ 0.8% | 2026-04-04 16:38 | |
| ⚖ | Recalibrated | $0.421 | ▼ 0.5% | 2026-04-04 16:02 | |
| 📄 | New Evidence | $0.423 | ▲ 0.8% | evidence_batch_update | 2026-04-04 09:08 |
| ⚖ | Recalibrated | $0.420 | ▼ 30.4% | 2026-04-03 23:46 | |
| 📄 | New Evidence | $0.604 | ▲ 7.0% | market_dynamics | 2026-04-03 09:19 |
| 💬 | Debate Round | $0.564 | ▼ 2.0% | market_dynamics | 2026-04-03 08:14 |
| 📊 | Score Update | $0.575 | ▲ 30.0% | market_dynamics | 2026-04-03 06:56 |
| 💬 | Debate Round | $0.442 | ▼ 6.4% | market_dynamics | 2026-04-03 06:32 |
| 💬 | Debate Round | $0.472 | ▼ 7.6% | market_dynamics | 2026-04-03 05:53 |
| 📊 | Score Update | $0.511 | ▼ 25.2% | market_dynamics | 2026-04-03 05:19 |
| 📊 | Score Update | $0.684 | ▼ 8.1% | market_dynamics | 2026-04-03 02:36 |
| 💬 | Debate Round | $0.745 | ▲ 43.7% | market_dynamics | 2026-04-03 00:31 |
Clinical Trials (5) Relevance: 38%
0
Active
Active
0
Completed
Completed
1,240
Total Enrolled
Total Enrolled
PHASE1
Highest Phase
Highest Phase
UNKNOWN
·
NCT04887675 · University of Novi Sad
120 enrolled · 2021-05-01 · → 2022-06-01
Since the HIV changed its course to the chronic disease, high incidence of metabolic syndrome both in HIV positive and negative subjects has become an issue. Given the successful peripheral suppressio
HIV I Infection HIV Associated Lipodystrophy Metabolic Syndrome
MRI
ENROLLING_BY_INVITATION
·
NCT06875739 · Fondazione Don Carlo Gnocchi Onlus
310 enrolled · 2025-02-14 · → 2026-10-01
The aim of the study is to validate a salivary test that allows for rapid and accurate objective diagnosis in the context of neurodegenerative diseases, a complex of diseases that includes Alzheimer's
Neurodegenerative Disorders Parkinson Disease Alzheimer Disease
RECRUITING
·
NCT00029965 · National Human Genome Research Institute (NHGRI)
200 enrolled · 2002-02-06
Study description:
This is a natural history study that will evaluate any patient with enzyme or DNA confirmed GM1 or GM2 gangliosidosis, sialidosis or galactosialidosis. Patients may be evaluated ev
Neurological Regression Myoclonus Cherry Red Spot
COMPLETED
·
NCT04281186 · Hospital Universitari Vall d'Hebron Research Institute
510 enrolled · 2020-11-16 · → 2024-12-12
The retina shares similar embryologic origin, anatomical features and physiological properties with the brain and hence offers a unique and accessible "window" to study the correlates and consequences
Retinal Function Cognitive Dysfunction Microperimetry
UNKNOWN
·
NCT04248270 · Chang Gung Memorial Hospital
100 enrolled · 2020-02-20 · → 2023-08-17
Dementia is a clinical syndrome which characterized by progressive cognitive impairment, behavior disturbance and dysfunction of daily activity. In aging population, Alzheimer's dementia (AD) is the m
Alzheimer's Disease Vascular Dementia Dementia
18F-PM-PBB3
📚 Cited Papers (37)
[WALANT - Wide Awake Local Anaesthesia No Tourniquet: Complications in elective and acute traumatological Hand Surgery Procedures].
Handchirurgie, Mikrochirurgie, plastische Chirurgie : Organ der Deutschsprachigen Arbeitsgemeinschaft fur Handchirurgie : Organ der Deutschsprachigen Arbeitsgemeinschaft fur Mikrochirurgie der Peripheren Nerven und Gefasse : Organ der V... (2022) · PMID:35168268
1 figure
Figures
Figures available at source paper (no open-access XML found).
deep_link
Engineering complex communities by directed evolution.
Nature ecology & evolution (2021) · PMID:33986540
9 figures
Extended Data Figure 1.
Non-additive function, costly function, and two empirically motivated functions. (A) Illustration of the different types of community function we have considered. In addition to th...
pmc_api
Extended Data Figure 2.
Alternative ecological scenarios with metabolic cross-feeding. Besides the rich medium without cross-feeding shown in the main text, we have included two other ecological scenarios...
pmc_api
Functional characterization of 84 PALB2 variants of uncertain significance.
Genetics in medicine : official journal of the American College of Medical Genetics (2020) · PMID:31636395
4 figures
Fig. 1
Homology directed repair assay of PALB2 variants. ( a ) Plot of all variants assayed in homologous recombination (HR) repair assay. Results for each independent assay are scaled 1...
pmc_api
Fig. 2
Influence of PALB2 variants on protein complex formation and protein half-life. ( a ) Western blot analysis of PALB2-interacting proteins after coimmunoprecipitation of FLAG-tagge...
pmc_api
Successful Nonoperative Treatment of Osteochondritis Dissecans of the Humeral Capitellum in a Young Baseball Player with Advanced Skeletal Maturity.
Progress in rehabilitation medicine (2021) · PMID:34825100
4 figures
Fig. 1.
Sonographic image of OCD of the humeral capitellum in the sagittal plane showing irregularity and discontinuity of the subchondral bone.
pmc_api
Fig. 2.
(A) Radiograph taken at the first examination showing an osteochondral lesion on the lateral side of the capitellum and new bone formation along the lateral side of capitellum (arr...
pmc_api
Canonical and atypical E2Fs regulate the mammalian endocycle.
Nature cell biology (2013) · PMID:23064266
No extracted figures yet
Emerging roles and underlying molecular mechanisms of DNAJB6 in cancer.
Oncotarget (2016) · PMID:27276715
No extracted figures yet
The integrin-binding defective FGF2 mutants potently suppress FGF2 signalling and angiogenesis.
Bioscience reports (2017) · PMID:28302677
No extracted figures yet
Genome-wide analysis of health-related biomarkers in the UK Household Longitudinal Study reveals novel associations.
Scientific reports (2019) · PMID:28887542
No extracted figures yet
Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.
Annals of clinical and translational neurology (2018) · PMID:30564623
No extracted figures yet
Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer's Disease Model.
Neuron (2019) · PMID:30737131
No extracted figures yet
Protein Aggregation Capture on Microparticles Enables Multipurpose Proteomics Sample Preparation.
Molecular & cellular proteomics : MCP (2019) · PMID:30833379
No extracted figures yet
5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs.
Nature cell biology (2019) · PMID:31358969
No extracted figures yet
📙 Related Wiki Pages (15)
EED geneAlibaba Tongyi Qianwen-Bio (Chinese Biomedical LLM ai_toolDNAJB6 Gene geneDNAJB6 Protein proteinNeurodegeneration diseaseDNAJB6 Gene geneDNAJB2 — DNAJ Heat Shock Protein Family Member B2 geneAmyotrophic Lateral Sclerosis redirectDNAJB5 (DnaJ Heat Shock Protein Family Member B5) geneFrontotemporal Dementia diseaseDiffuse Amyloid Deposits in Alzheimer's Disease mechanismAlzheimer's Disease diseaseGenes indexDNAJB12 — DnaJ Heat Shock Protein Family (Hsp40) M geneParkinson's Disease disease
📓 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
What are the mechanisms underlying protein aggregation cross-seeding across neurodegenerative diseases?
📊 Resource Economics & ROI
Moderate Efficiency
Resource Efficiency Score
0.63
36.0th percentile (747 hypotheses)
Tokens Used
5,377
KG Edges Generated
471
Citations Produced
16
Cost Ratios
Cost per KG Edge
122.20 tokens
Lower is better (baseline: 2000)
Cost per Citation
672.12 tokens
Lower is better (baseline: 1000)
Cost per Score Point
9829.98 tokens
Tokens / composite_score
Score Impact
Efficiency Boost to Composite
+0.063
10% weight of efficiency score
Adjusted Composite
0.607
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 | $0.434 | 0.510 |
Wiki Pages
EEDgeneAlibaba Tongyi Qianwen-Bio (Chinese Biomedical LLMai_toolDNAJB6 GenegeneDNAJB6 ProteinproteinNeurodegenerationdiseaseDNAJB6 GenegeneDNAJB2 — DNAJ Heat Shock Protein Family Member B2geneAmyotrophic Lateral SclerosisredirectDNAJB5 (DnaJ Heat Shock Protein Family Member B5)geneFrontotemporal DementiadiseaseDiffuse Amyloid Deposits in Alzheimer's DiseasemechanismAlzheimer's DiseasediseaseGenesindexDNAJB12 — DnaJ Heat Shock Protein Family (Hsp40) MgeneParkinson's Diseasedisease
KG Entities (39)
DNAJB6DNAJB6_proteinG3BP1HSPA8HSPG2PHB2RNA_bindingRNA_splicingTDP-43TGM2TREM2TREM2_proteinalpha-synucleinalzheimers_diseaseamyloid_formationamyloid_nucleationautophagybeta_sheet_structurecross_seedingfrontotemporal_dementia
Linked Experiments (1)
Related Hypotheses
TREM2-Dependent Astrocyte-Microglia Cross-talk in Neurodegeneration
Score: 0.990 | neurodegeneration
TREM2-Dependent Microglial Senescence Transition
Score: 0.950 | neurodegeneration
PLCG2 Allosteric Modulation as a Precision Therapeutic for TREM2-Dependent Microglial Dysfunction
Score: 0.941 | neurodegeneration
Multi-Biomarker Composite Index Surpassing Amyloid PET for Treatment Response Prediction
Score: 0.933 | neurodegeneration
CYP46A1 Gene Therapy for Age-Related TREM2-Mediated Microglial Senescence Reversal
Score: 0.921 | neurodegeneration
Estimated Development
Estimated Cost
$0
Timeline
2.0 years
🧪 Falsifiable Predictions (4)
4 total
0 confirmed
0 falsified
If hypothesis is true, intervention otherwise facilitate heterologous protein recruitment
pending
conf: 0.45
Expected outcome: otherwise facilitate heterologous protein recruitment
Falsified by: Intervention fails to otherwise facilitate heterologous protein recruitment
If hypothesis is true, intervention require a multi-faceted experimental approach combining in vitro biochemical assays, cell culture models, and in vivo studies
pending
conf: 0.45
Expected outcome: require a multi-faceted experimental approach combining in vitro biochemical assays, cell culture models, and in vivo studies
Falsified by: Intervention fails to require a multi-faceted experimental approach combining in vitro biochemical assays, cell culture models, and in vivo studies
If hypothesis is true, intervention provide broad-spectrum protection against multiple neurodegenerative diseases simultaneously
pending
conf: 0.45
Expected outcome: provide broad-spectrum protection against multiple neurodegenerative diseases simultaneously
Falsified by: Intervention fails to provide broad-spectrum protection against multiple neurodegenerative diseases simultaneously
If hypothesis is true, intervention address the fundamental mechanism underlying protein aggregation and cross-seeding
pending
conf: 0.45
Expected outcome: address the fundamental mechanism underlying protein aggregation and cross-seeding
Falsified by: Intervention fails to address the fundamental mechanism underlying protein aggregation and cross-seeding
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 DNAJB6
Molecular pathway showing key causal relationships underlying this hypothesis
graph TD
DNAJB6["DNAJB6"] -->|encodes| DNAJB6_protein["DNAJB6_protein"]
DNAJB6_protein_1["DNAJB6_protein"] -.->|inhibits| amyloid_formation["amyloid_formation"]
DNAJB6_protein_2["DNAJB6_protein"] -->|binds| tau["tau"]
DNAJB6_protein_3["DNAJB6_protein"] -->|binds| alpha_synuclein["alpha-synuclein"]
DNAJB6_protein_4["DNAJB6_protein"] -->|binds| TDP_43["TDP-43"]
HSPA8["HSPA8"] -->|interacts with| DNAJB6_protein_5["DNAJB6_protein"]
style DNAJB6 fill:#ce93d8,stroke:#333,color:#000
style DNAJB6_protein fill:#4fc3f7,stroke:#333,color:#000
style DNAJB6_protein_1 fill:#4fc3f7,stroke:#333,color:#000
style amyloid_formation fill:#ffd54f,stroke:#333,color:#000
style DNAJB6_protein_2 fill:#4fc3f7,stroke:#333,color:#000
style tau fill:#4fc3f7,stroke:#333,color:#000
style DNAJB6_protein_3 fill:#4fc3f7,stroke:#333,color:#000
style alpha_synuclein fill:#4fc3f7,stroke:#333,color:#000
style DNAJB6_protein_4 fill:#4fc3f7,stroke:#333,color:#000
style TDP_43 fill:#4fc3f7,stroke:#333,color:#000
style HSPA8 fill:#ce93d8,stroke:#333,color:#000
style DNAJB6_protein_5 fill:#4fc3f7,stroke:#333,color:#000
3D Protein Structure
🧬 DNAJB6 — PDB 6GFB Click to expand 3D viewer
Source Analysis
Protein aggregation cross-seeding across neurodegenerative diseases
neurodegeneration | 2026-04-01 | completed
Community Feedback
0
0 upvotes · 0 downvotes
💬 0 comments
⚠ 0 flags
✏ 0 edit suggestions
No comments yet. Be the first to comment!