ID: h-f3eff15058ab
Hypothesis
MAP6-mediated microtubule stabilization as therapeutic target
Aberrant MAP6 function may contribute to tau-independent cytoskeletal defects in neurodegeneration, and stabilizing MAP6-microtubule interactions pharmacologically could compensate for Tau pathology.
EvidenceModerate (45%)📖 0 cit🗣 1 debates✓ 6 support✗ 2 oppose
🧪 Overview
Aberrant MAP6 function may contribute to tau-independent cytoskeletal defects in neurodegeneration, and stabilizing MAP6-microtubule interactions pharmacologically could compensate for Tau pathology
Prediction: Small molecules enhancing MAP6-microtubule binding will ameliorate cytoskeletal defects in tau knockout neurons and improve neuronal survival in amyloid toxicity models
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["MAPT/Tau Occupancy<br/>Dynamic Microtubule Binding"]
B["MAP6 Occupancy<br/>Cold-Stable Domain Support"]
C["Shared Microtubule Lattice<br/>Domain Allocation Competition"]
D["GSK3B/CRMP2 Cue Integration<br/>Plasticity Signaling"]
E["Axonal Remodeling Balance<br/>Stable vs Labile Segments"]
F["Transport and Branching<br/>Adaptive Circuit Plasticity"]
G["Tau-MAP6 Imbalance<br/>Rigid or Unstable Cytoskeleton"]
A --> C
B --> C
C --> D
D --> E
E --> F
G -.->|"disrupts"| C
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style B fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#1b5e20,stroke:#81c784,color:#81c784
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix6 supports2 contradicts
Supports
Aberrant MAP6 function may contribute to tau-independent cytoskeletal defects in neurodegeneration, and stabilizing MAP6-microtubule interactions pharmacologically could compensate for Tau pathology
Supports
Beyond Neuronal Microtubule Stabilization: MAP6 and CRMPS, Two Converging Stories.
Supports
Dynamic Palmitoylation Targets MAP6 to the Axon to Promote Microtubule Stabilization during Neuronal Polarization.
Supports
A cytoskeleton-membrane interaction conserved in fast-spiking neurons controls movement, emotion, and memory.
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 — MAP6
No curated PDB or AlphaFold mapping for MAP6 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for MAP6 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 MAP6.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
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Volatility
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▲1.1%💾 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 5xFAD amyloid transgenic mice (8 months old) are administered a MAP6 stabilizer (intraperitoneal injection at 20 mg/kg daily for 8 weeks), THEN spatial memory performance on the Morris water maze w | Morris water maze escape latency: ≥25% reduction; Cortical neuron count (NeuN+ cells): ≥20% increase; Insoluble amyloid load: ≤10% change (to confirm direct cyt | — no observation — | pending | 0.55 |
| IF primary cortical neurons from tau knockout mice are treated with a small molecule that enhances MAP6-microtubule binding (e.g., MS-12 or similar compound at 10 μM for 7 days), THEN acetylated α-tub | Acetylated α-tubulin levels: ≥40% increase; Cell viability (MTS assay): ≥30% improvement; Microtubule polymerization rate: ≥25% increase | — no observation — | pending | 0.65 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF primary cortical neurons from tau knockout mice are treated with a small molecule that enhances MAP6-microtubule binding (e.g., MS-12 or similar compound at 10 μM for 7 days), THEN acetylated α-tubulin levels will increase by at least 40% and neuronal viability will improve by at least 30% compar
Predicted outcome: Acetylated α-tubulin levels: ≥40% increase; Cell viability (MTS assay): ≥30% improvement; Microtubule polymerization rate: ≥25% increase
Falsification: Acetylated α-tubulin levels fail to increase significantly (p>0.05) or neuronal viability shows no improvement (<10% change) or decreases in MAP6-treated tau knockout neurons compared to vehicle contr
pendingconf 55%
IF 5xFAD amyloid transgenic mice (8 months old) are administered a MAP6 stabilizer (intraperitoneal injection at 20 mg/kg daily for 8 weeks), THEN spatial memory performance on the Morris water maze will improve by at least 25% (reduced escape latency) and cortical neuron survival will increase by a
Predicted outcome: Morris water maze escape latency: ≥25% reduction; Cortical neuron count (NeuN+ cells): ≥20% increase; Insoluble amyloid load: ≤10% change (to confirm
Falsification: No significant improvement in spatial memory (escape latency reduction <15% or p>0.05), no increase in cortical neuronal survival, or behavioral improvement is accompanied by reduced amyloid load sugg
▸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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