ID: h-gwas-ptk2b-endocytosis-axis-5dee99f5
Hypothesis
Tau-trafficking GWAS loci define a druggable PTK2B endocytosis-kinase axis in AD
PTK2B, BIN1, PICALM, and SORL1 form a trafficking and kinase-linked AD risk cluster in the dataset.
EvidenceStrong (61%)📖 0 cit🗣 1 debates✓ 7 support✗ 1 oppose
🧪 Overview
PTK2B, BIN1, PICALM, and SORL1 form a trafficking and kinase-linked AD risk cluster in the dataset. The notebook identifies this as a druggable axis because PTK2B is a kinase, BIN1 and PICALM implicate endocytosis, and SORL1 ties the module to APP trafficking. Hypothesis: Pyk2 pathway modulation will normalize tau phosphorylation and endosomal stress in APOE4 or tauopathy human neuronal co-cultures.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["PTK2B FAK2 Kinase<br/>Postsynaptic Density Component"]
B["Calcium Influx<br/>NMDAR and Voltage-Gated Channel"]
C["PTK2B Autophosphorylation<br/>pY402 Kinase Activation"]
D["PI3K and SRC Coupling<br/>Downstream Effector Cascade"]
E["PICALM-Mediated Endocytosis<br/>Clathrin AP2 Recruitment"]
F["BIN1 Membrane Tubulation<br/>Endosomal Tau Routing"]
G["Tau Seed Propagation<br/>Trans-Synaptic Spread"]
A --> C
B --> A
C --> D
D --> E
E --> F
F --> G
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style C fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix7 supports1 contradicts
Supports
PTK2B, BIN1, PICALM, and SORL1 are AD risk loci linked to tau, endocytosis, calcium signaling, and APP trafficking in curated notes.
dataset:ad_genetic_risk_loci
Supports
Druggability ranking favors PTK2B because kinase biology offers a tractable perturbation point across the trafficking module.
notebook:gwas-ad-risk-loci-analysis
Supports
Microglia PTK2B/Pyk2 in the Pathogenesis of Alzheimer's Disease.
Supports
Proteomic analysis identifies HSP90AA1, PTK2B, and ANXA2 in the human entorhinal cortex in Alzheimer's disease: Potential role in synaptic homeostasis and Aβ pathology through microglial and astroglial cells.
Supports
Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy.
Supports
Pyk2 is a Novel Tau Tyrosine Kinase that is Regulated by the Tyrosine Kinase Fyn.
Supports
Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β.
Contradicts
Common GWAS effect sizes are modest and causal direction may differ across neuronal and glial contexts.
notebook:gwas-ad-risk-loci-analysis
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — PTK2B
No curated PDB or AlphaFold mapping for PTK2B yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for PTK2B/BIN1/PICALM from GTEx v10.
💉 Clinical Trials
No clinical trials data linked to this hypothesis yet.
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 PTK2B.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
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▼9.4%💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF PTK2B kinase activity is pharmacologically inhibited (PF-07105691 or genetic knockdown) in APOE4 human iPSC-derived excitatory neurons co-cultured with APOE4 astrocytes, THEN phospho-tau217/181 lev | Significant reduction in p-tau217 (≥40% decrease) and normalization of enlarged early endosomes (RAB5+ compartments to <1.2μm mean diameter) measured by high-co | — no observation — | pending | 0.72 |
| IF BIN1 or PICALM expression is genetically modulated (BIN1 knockout or PICALM overexpression) in human P301L tau iPSC neurons, THEN PTK2B autophosphorylation (pY402) and downstream phospho-CREB level | BIN1 KO will increase pY402-PTK2B by >60% and p-CREB by >50%; PICALM overexpression will decrease pY402-PTK2B by >40% and p-CREB by >35%, measured by western bl | — no observation — | pending | 0.68 |
🔮 Falsifiable Predictions (2)
pendingconf 72%
IF PTK2B kinase activity is pharmacologically inhibited (PF-07105691 or genetic knockdown) in APOE4 human iPSC-derived excitatory neurons co-cultured with APOE4 astrocytes, THEN phospho-tau217/181 levels will decrease by >40% and endosomal vesicle size will normalize to <1.2μm within 14 days of inte
Predicted outcome: Significant reduction in p-tau217 (≥40% decrease) and normalization of enlarged early endosomes (RAB5+ compartments to <1.2μm mean diameter) measured
Falsification: No significant change (<20%) in phospho-tau levels or persistent endosomal enlargement (>1.5μm) after PTK2B inhibition would falsify the hypothesis that PTK2B modulates tau phosphorylation through end
pendingconf 68%
IF BIN1 or PICALM expression is genetically modulated (BIN1 knockout or PICALM overexpression) in human P301L tau iPSC neurons, THEN PTK2B autophosphorylation (pY402) and downstream phospho-CREB levels will change in opposite directions, confirming a regulatory axis between endocytic proteins and PT
Predicted outcome: BIN1 KO will increase pY402-PTK2B by >60% and p-CREB by >50%; PICALM overexpression will decrease pY402-PTK2B by >40% and p-CREB by >35%, measured by
Falsification: No reciprocal changes in PTK2B phosphorylation following BIN1/PICALM modulation (change <20%) or paradoxical directionality would falsify the existence of a BIN1/PICALM-PTK2B regulatory axis in human
▸Metadatasource: v1_phase_c_backfill · origin_type: forge_notebook
| source | v1_phase_c_backfill |
| origin_type | forge_notebook |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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