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
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:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for MAPT 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 MAPT.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.
| 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 |