Loss of tau function (as in disease states) selectively destabilizes the labile microtubule population, disrupting axonal transport while sparing stable domains
Prediction: Tau-targeted interventions will selectively impair transport of organelles requiring labile microtubules (mitochondria, endosomes) while sparing lysosome transport
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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: 45%6 supporting / 2 opposing
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Abstract
MAPT mutations, tauopathy, and mechanisms of neuro…
Loss of tau function (as in disease states) selectively destabilizes the labile microtubule population, disrup…▼
Loss of tau function (as in disease states) selectively destabilizes the labile microtubule population, disrupting axonal transport while sparing stable domains
MAPT mutations, tauopathy, and mechanisms of neurodegeneration.MEDIUM
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IF CRISPR/Cas9-mediated MAPT knockout is performed in human iPSC-derived cortical neurons, THEN the mean anterograde velocity of mitochondria in distal axons will decrease by at least 40% relative to wild-type controls within 10 days, while the velocity of lysosomes will not change by more than 15%.
pendingconf: 0.60
Expected outcome: Selective ≥40% decrease in mitochondrial transport without significant change in lysosome transport.
Falsified by: If both mitochondrial and lysosome transport are reduced by ≥30% or if mitochondrial transport reduction is <30%, the hypothesis of selective destabilization of labile microtubules is falsified.
Method: CRISPR/Cas9 editing of MAPT in iPSC-derived cortical neurons; live-cell imaging of axonal transport using MitoTracker and Lysotracker; quantification of transport parameters over 10 days post-editing.
IF a selective labile microtubule stabilizer (e.g., 10 nM epothilone D) is applied to MAPT knockout neurons, THEN the mitochondrial transport deficit will be rescued to ≥80% of wild-type velocity within 48 h of treatment.
pendingconf: 0.55
Expected outcome: Restoration of mitochondrial transport velocity to ≥80% of wild-type levels after epothilone D.
Falsified by: If mitochondrial transport remains <50% of wild-type after 48 h of epothilone D treatment, the hypothesis that labile microtubule destabilization underlies the transport deficit is falsified.
Method: MAPT knockout iPSC-derived cortical neurons treated with 10 nM epothilone D; live-cell imaging of axonal mitochondria before and 48 h after drug addition; quantification of transport velocity.