ID: h-5bdd4e163c5a
Hypothesis
Competition-based domain allocation
Tau and MAP6 compete for microtubule binding sites in a concentration-dependent manner, with relative local abundance determining domain stability.
EvidenceStrong (60%)📖 6 cit🗣 1 debates✓ 6 support✗ 2 oppose
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🧪 Overview
Tau and MAP6 compete for microtubule binding sites in a concentration-dependent manner, with relative local abundance determining domain stability
Prediction: Artificially equalizing tau:MAP6 ratio on individual microtubules will produce intermediate stability domains with mixed molecular signatures
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["MAPT/Tau Protein<br/>Microtubule Stabilizer"]
B["CDK5/GSK3B Activation<br/>Kinase Dysregulation"]
C["Tau Hyperphosphorylation<br/>Ser396/Thr231/Ser202"]
D["Tau Detachment<br/>Microtubule Destabilized"]
E["Tau Oligomers<br/>Paired Helical Filaments"]
F["Neurofibrillary Tangles<br/>Intraneuronal Inclusions"]
G["Axonal Transport Failure<br/>Synaptic Dysfunction"]
H["Neurodegeneration<br/>Tauopathy Spread"]
A --> B
B --> C
C --> D
D --> E
E --> F
D --> G
G --> H
F --> H
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style C fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix6 supports2 contradicts
Supports
Tau and MAP6 compete for microtubule binding sites in a concentration-dependent manner, with relative local abundance determining domain stability
Supports
Antagonistic roles of tau and MAP6 in regulating neuronal development.
Supports
Tau filaments with the Alzheimer fold in human MAPT mutants V337M and R406W.
Supports
MAPT mutations, tauopathy, and mechanisms of neurodegeneration.
Supports
Endolysosomal impairment by binding of amyloid beta or MAPT/Tau to V-ATPase and rescue via the HYAL-CD44 axis in Alzheimer disease.
Supports
Tau-targeting antisense oligonucleotide MAPT(Rx) in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial.
Contradicts
Tau/MAP6 antagonism is shown in neuronal development models, but this does not establish that the same balance drives adult neurodegeneration progression or treatment response.
Contradicts
A microtubule-stabilizing peptide strategy failed to show clinical benefit in progressive supranuclear palsy, cautioning against simple cytoskeletal-stabilization translation in tauopathy.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — MAPT
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for MAPT from GTEx v10.
💉 Clinical Trials (5)Relevance: 75%
0
Active
Active
0
Completed
Completed
0
Total Enrolled
Total Enrolled
PHASE1
Highest Phase
Highest Phase
COMPLETED·NCT06584656 · Universidad de Granada
Healthy Aging Cognitive Function 1, Social Cerebrovascular Circulation
Aerobic exercise condition Resistance exercise condition
Safety Study of AADvac1, a Tau Peptide-KLH-Conjugate Active Vaccine to Treat Alzheimer's DiseasePHASE1
COMPLETED·NCT01850238 · Axon Neuroscience SE
Alzheimer Disease
AADvac1 Placebo
RECRUITING·NCT04906863 · Columbia University
Dementia, Early Onset
Blood draw Neurocognitive testing Medical questionnaire
COMPLETED·NCT04413344 · Kyoto University
Familial Alzheimer Disease (FAD) PSEN1 Mutation
Bromocriptine Mesilate Placebos
COMPLETED·NCT03978052 · Parc de Salut Mar
Alzheimer Disease Cognitive Decline
EGCG Placebo EGCG Healthy lifestyle recommendations
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 MAPT.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
No arena matches recorded yet. Browse Arenas →
📊 Market Indicators
7d Trend
↔
Stable
7d Momentum
▼ 0.3%
Volatility
High
0.0822
Events (7d)
2
Price History
▼3.0%💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we reconstitute individual microtubules in vitro with purified tau and MAP6 at defined stoichiometric ratios (e.g., 1:1, 2:1, 1:2) while holding total protein concentration constant, THEN the mecha | Linear or monotonic correlation between tau:MAP6 ratio and microtubule mechanical properties measured by optical tweezers or thermal denaturation, with mixed do | — no observation — | pending | 0.45 |
| IF we apply pseudo-phosphorylated tau (using casein kinase II or GSK3β treatment at 6-8 sites) or introduce frontotemporal dementia-linked MAPT mutations (P301L, V337M) to primary cortical neurons, TH | ≥30% increase in tau:MAP6 ratio on axonal microtubules under disease-mimicking conditions, detectable by decreased MAP6 epitope accessibility or increased tau:M | — no observation — | pending | 0.38 |
🔮 Falsifiable Predictions (2)
pendingconf 45%
IF we reconstitute individual microtubules in vitro with purified tau and MAP6 at defined stoichiometric ratios (e.g., 1:1, 2:1, 1:2) while holding total protein concentration constant, THEN the mechanical rigidity (flexural rigidity) and thermal stability (critical temperature of disassembly) will
Predicted outcome: Linear or monotonic correlation between tau:MAP6 ratio and microtubule mechanical properties measured by optical tweezers or thermal denaturation, wit
Falsification: Microtubules show discrete, non-graded stability states regardless of ratio; intermediate ratios produce phase-separated domains but no intermediate stability values; or MAP6 and tau occupy non-overla
pendingconf 38%
IF we apply pseudo-phosphorylated tau (using casein kinase II or GSK3β treatment at 6-8 sites) or introduce frontotemporal dementia-linked MAPT mutations (P301L, V337M) to primary cortical neurons, THEN the relative occupancy of tau versus MAP6 on axonal microtubules will shift toward increased tau
Predicted outcome: ≥30% increase in tau:MAP6 ratio on axonal microtubules under disease-mimicking conditions, detectable by decreased MAP6 epitope accessibility or incre
Falsification: Disease-associated tau modifications do not alter tau:MAP6 binding site competition; MAP6 expression compensates to maintain constant net occupancy; or tau and MAP6 bind non-competitively to distinct
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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