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
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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 ANK2 from GTEx v10.
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8 citations7 with PMID7 mediumValidation: 0%6 supporting / 2 opposing
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Evidence Matrix — sortable by strength/year, click Abstract to expand
Axon initial segment (AIS) infrastructure provides additional regulatory context that consolidates MAP-established domains; in fibroblasts, domains are less stable without this architectural support
ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plastic…MEDIUM▼
ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks.
Ankyrin-G and AIS organization depend on many binding partners, making ANK2-only domain stabilization an incom…MEDIUM▼
Ankyrin-G and AIS organization depend on many binding partners, making ANK2-only domain stabilization an incomplete model of neuronal compartment maintenance.
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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 in tau/MAP6 domain stability (measured by increased mobile fraction in FRAP and shorter domain lifetime) within 48-72 hours, compared to untreated neurons.
pendingconf: 0.45
Expected outcome: Rapid destabilization of microtubule-associated protein domains following AIS disruption, evidenced by increased FRAP mobile fraction and decreased domain dwell time in live-cell imaging.
Falsified by: Domain stability metrics remain unchanged (within 10%) after AIS disruption, or domains become MORE stable, indicating AIS is not the primary architectural constraint for MAP domain maintenance in neurons.
Method: Dissociated mouse hippocampal neurons (DIV14-21) transfected with MAP6-eGFP, treated with 1μM tetrodotoxin or transfected with Cas9-sgAnkG for 48-72 hours, followed by FRAP analysis of AIS-localized MAP6 domains, with comparison to vehicle-treated or Cas9-sgLacZ controls.
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 FRAP recovery half-time increasing by >40%) within 5-7 days post-transduction, compared to GFP-transduced control fibroblasts.
pendingconf: 0.35
Expected outcome: Enhanced domain stability in fibroblasts expressing neuronal ANK2, manifested as slower fluorescence recovery in FRAP assays and reduced domain dissolution events over 72-hour imaging windows.
Falsified by: FRAP recovery half-times in ANK2-expressing fibroblasts remain statistically indistinguishable from control fibroblasts (p > 0.05), or domain stability metrics show <20% improvement, indicating AIS architecture alone is insufficient without additional neuronal-specific factors.
Method: Primary human dermal fibroblasts or iPSC-derived fibroblasts transduced with lenti-ANK2-G or lenti-GFP control, followed by FRAP analysis of mApple-tau or MAP6-mNeon domains at 5-7 days post-infection, with n≥30 cells per condition across 3 biological replicates.
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3D Protein Structure
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ANK2 — Search for structure
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