The relative abundance of tau versus MAP6 on individual microtubules determines the balance between stable and labile domains, creating a spatial code for where dynamic remodeling (axon guidance, branching) versus stable support (process integrity) occurs
Prediction: Manipulating the tau:MAP6 expression ratio will shift the entire spectrum of neuronal plasticity phenotypes in a predictable dose-response manner
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Curated Mechanism Pathway
Curated pathway diagram from expert analysis
flowchart TD
A["MAPT/Tau Protein Microtubule Stabilizer"]
B["CDK5/GSK3B Activation Kinase Dysregulation"]
C["Tau Hyperphosphorylation Ser396/Thr231/Ser202"]
D["Tau Detachment Microtubule Destabilized"]
E["Tau Oligomers Paired Helical Filaments"]
F["Neurofibrillary Tangles Intraneuronal Inclusions"]
G["Axonal Transport Failure Synaptic Dysfunction"]
H["Neurodegeneration 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
Median TPM across 13 brain regions for MAPT from GTEx v10.
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8 citations7 with PMID5 mediumValidation: 50%6 supporting / 2 opposing
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5
No opposing evidence
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Evidence Matrix — sortable by strength/year, click Abstract to expand
Evidence Types
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MECH 5CLIN 1GENE 2EPID 0
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PMIDs
Abstract
Antagonistic roles of tau and MAP6 in regulating n…
The relative abundance of tau versus MAP6 on individual microtubules determines the balance between stable and…▼
The relative abundance of tau versus MAP6 on individual microtubules determines the balance between stable and labile domains, creating a spatial code for where dynamic remodeling (axon guidance, branching) versus stable support (process integrity) occurs
Antagonistic roles of tau and MAP6 in regulating neuronal development.MEDIUM
Denarier E et al., Proc Natl Acad Sci U S A 1998 May 26 · PMID:9600916
No claimMODERATE
Andrieux A et al., Genes Dev 2002 Sep 15 · PMID:12231625
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IF the tau:MAP6 expression ratio is experimentally shifted via CRISPR activation of MAP6 promoter in mature hippocampal neurons (increasing MAP6 relative to endogenous tau), THEN microtubule dynamic instability will increase by ≥40% measured by EB3 comet tracking lifetime within 72 hours, AND stable microtubule post-translational modification signatures (acetylated tubulin) will decrease by ≥30% compared to controls.
pendingconf: 0.45
Expected outcome: Dose-dependent increase in microtubule dynamics (shorter EB3 comet lifetimes, increased catastrophe frequency) and decrease in stable acetylated microtubule networks as MAP6 expression rises
Falsified by: If microtubule dynamic parameters remain within ±15% of baseline despite >2-fold increase in MAP6 expression, the hypothesis is falsified
Method: Primary mouse hippocampal neuron culture transfected with CRISPRa-MAP6 or CRISPRa-tau constructs at DIV14-18; EB3-mApple live imaging with automated comet tracking; immunocytochemistry for ac-tubulin quantification
IF MAPT-knockout neurons (which have low tau) are crossed with MAP6-knockout neurons to create a double knockout, THEN rescued expression of MAP6 at 3x endogenous levels will normalize axon branch dynamics to wildtype levels (within ±20%) within 5 days, whereas rescued MAP6 at 0.3x levels will fail to normalize dynamics.
pendingconf: 0.40
Expected outcome: Rescue with high MAP6 restores dynamic remodeling rates to wildtype baseline; rescue with low MAP6 leaves dynamics elevated
Falsified by: If both high and low MAP6 rescue conditions produce identical axon branch dynamics (within experimental noise), the ratio-dependent model is falsified
Method: Human iPSC-derived cortical neurons with CRISPR KO of MAPT or MAP6; AAV-mediated inducible MAP6 expression at defined levels; longitudinal confocal imaging of axon branching over 5 days post-induction