Axon initial segment (AIS) infrastructure provides additional regulatory context that consolidates MAP-established domains; in fibroblasts, domains are less stable without this architectural support
Prediction: Transplanting AIS components into fibroblasts will produce more robust and long-lasting tau/MAP6 domain segregation
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.
No curated PDB or AlphaFold mapping for ANK2 yet. Search RCSB →
Median TPM across 13 brain regions for ANK2 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 ANK2.
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 express the neuronal ANK2 isoform (ANK2-G) in human fibroblasts via lentiviral transduction, THEN we will observe a statistically significant increase in tau/MAP6 domain stability (measured by F | Enhanced domain stability in fibroblasts expressing neuronal ANK2, manifested as slower fluorescence recovery in FRAP assays and reduced domain dissolution even | — no observation — | pending | 0.35 |
| IF we acutely disrupt AIS integrity in mature hippocampal neurons using pharmacological (sodium channel blocker) or genetic (ankyrin-G CRISPR knockout) approaches, THEN we will observe a >50% decrease | Rapid destabilization of microtubule-associated protein domains following AIS disruption, evidenced by increased FRAP mobile fraction and decreased domain dwell | — no observation — | pending | 0.45 |