ID: hyp-SDA-2026-04-09-gap-debate-20260409-2
Hypothesis
Combinatorial PTM signatures distinguish pathological from physiological tau states
A quantitative threshold of phosphorylation (S396/S404), acetylation (K280), and truncation (D421) defines a pathological tau PTM signature that predicts therapeutic vulnerability better than any single modification alone.
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 1 oppose
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🧪 Overview
A quantitative threshold of phosphorylation (S396/S404), acetylation (K280), and truncation (D421) defines a pathological tau PTM signature that predicts therapeutic vulnerability better than any single modification alone.
🧬 Mechanism
🔗 Mechanism from KG for MAPT
Auto-built from this analysis's top knowledge-graph edges.
graph TD
tau_protein["tau_protein"] -->|undergoes| post_translational_modifi["post_translational_modifications"]
post_translational_modifi_1["post_translational_modifications"] -->|contributes to| pathological_tau["pathological_tau"]
pathological_tau_2["pathological_tau"] -->|causes| neurodegeneration["neurodegeneration"]
CASP2["CASP2"] -->|causes| TAU_Aggregation["TAU Aggregation"]
CASP3["CASP3"] -->|causes| TAU_Aggregation_3["TAU Aggregation"]
EP300["EP300"] -->|causes| K280_acetylated_tau["K280 acetylated tau"]
D421_truncation["D421 truncation"] -->|biomarker for| Alzheimer_s_disease["Alzheimer's_disease"]
K280_acetylation["K280 acetylation"] -->|associated with| Alzheimer_s_disease_4["Alzheimer's_disease"]
CASP2_5["CASP2"] -->|causes| Neurofibrillary_Tangle_Fo["Neurofibrillary Tangle Formation"]
EP300_6["EP300"] -->|regulates| TAU_Acetylation["TAU Acetylation"]
post_translational_modifi_7["post_translational_modifications"] -->|causes| pathological_tau_8["pathological_tau"]
sess_SDA_2026_04_09_gap_d["sess_SDA-2026-04-09-gap-debate-20260409-201742-1e8eb3bd_20260412-091129"] -->|causal extracted| processed["processed"]
style tau_protein fill:#4fc3f7,stroke:#333,color:#000
style post_translational_modifi fill:#81c784,stroke:#333,color:#000
style post_translational_modifi_1 fill:#81c784,stroke:#333,color:#000
style pathological_tau fill:#4fc3f7,stroke:#333,color:#000
style pathological_tau_2 fill:#4fc3f7,stroke:#333,color:#000
style neurodegeneration fill:#ef5350,stroke:#333,color:#000
style CASP2 fill:#ce93d8,stroke:#333,color:#000
style TAU_Aggregation fill:#4fc3f7,stroke:#333,color:#000
style CASP3 fill:#ce93d8,stroke:#333,color:#000
style TAU_Aggregation_3 fill:#4fc3f7,stroke:#333,color:#000
style EP300 fill:#ce93d8,stroke:#333,color:#000
style K280_acetylated_tau fill:#4fc3f7,stroke:#333,color:#000
style D421_truncation fill:#4fc3f7,stroke:#333,color:#000
style Alzheimer_s_disease fill:#ef5350,stroke:#333,color:#000
style K280_acetylation fill:#4fc3f7,stroke:#333,color:#000
style Alzheimer_s_disease_4 fill:#ef5350,stroke:#333,color:#000
style CASP2_5 fill:#ce93d8,stroke:#333,color:#000
style Neurofibrillary_Tangle_Fo fill:#4fc3f7,stroke:#333,color:#000
style EP300_6 fill:#ce93d8,stroke:#333,color:#000
style TAU_Acetylation fill:#4fc3f7,stroke:#333,color:#000
style post_translational_modifi_7 fill:#4fc3f7,stroke:#333,color:#000
style pathological_tau_8 fill:#4fc3f7,stroke:#333,color:#000
style sess_SDA_2026_04_09_gap_d fill:#4fc3f7,stroke:#333,color:#000
style processed fill:#4fc3f7,stroke:#333,color:#000⚖️ Evidence
⚖️ Evidence Matrix5 supports0 contradicts
Supports
Interactions between Microtubule-Associated Protein Tau (MAPT) and Small Molecules.
Supports
MAPT mutations, tauopathy, and mechanisms of neurodegeneration.
Supports
Tau-targeting antisense oligonucleotide MAPT(Rx) in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial.
Supports
Tau filaments with the Alzheimer fold in human MAPT mutants V337M and R406W.
Supports
Isoform-specific patterns of tau burden and neuronal degeneration in MAPT-associated frontotemporal lobar degeneration.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — MAPT
💉 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 MAPT.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
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📊 Market Indicators
7d Trend
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Stable
7d Momentum
▲ 0.0%
Volatility
Medium
0.0449
Events (7d)
0
Price History
▲7.2%💾 Resource Usage
LLM Tokens
17,312
$0.0625
Total Cost
$0.0625
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF human iPSC-derived cortical neurons are exposed to pathological seeds AND a combinatorial PTM threshold is met (phospho-S396/S404 ≥ 70% of total tau, acetyl-K280 ≥ 40%, and truncation at D421 ≥ 30% | Combinatorial signature (+) cells show significantly higher tau seeding/aggregation readouts (e.g., FRET-based aggregation assay, Sarkosyl-insoluble tau fractio | — no observation — | pending | 0.68 |
| IF preclinical cohorts of P301S transgenic mice are stratified by the combinatorial tau PTM signature (threshold as defined above) versus single-modification stratification prior to anti-tau antibody | Mice meeting the full combinatorial signature show superior therapeutic response to anti-tau intervention, as measured by 50% reduction in Sarkosyl-insoluble ta | — no observation — | pending | 0.55 |
🔮 Falsifiable Predictions (2)
pendingconf 68%
IF human iPSC-derived cortical neurons are exposed to pathological seeds AND a combinatorial PTM threshold is met (phospho-S396/S404 ≥ 70% of total tau, acetyl-K280 ≥ 40%, and truncation at D421 ≥ 30% detected by targeted MS), THEN these neurons will exhibit ≥3-fold higher tau aggregation efficiency
Predicted outcome: Combinatorial signature (+) cells show significantly higher tau seeding/aggregation readouts (e.g., FRET-based aggregation assay, Sarkosyl-insoluble t
Falsification: Neurons with single PTM elevation (e.g., phospho-S396/S404 only, without acetylation or truncation) show equivalent aggregation efficiency to the combinatorial signature group, eliminating the added v
pendingconf 55%
IF preclinical cohorts of P301S transgenic mice are stratified by the combinatorial tau PTM signature (threshold as defined above) versus single-modification stratification prior to anti-tau antibody treatment (e.g., AJ196), THEN the combinatorial-stratified group will show ≥40% improvement in thera
Predicted outcome: Mice meeting the full combinatorial signature show superior therapeutic response to anti-tau intervention, as measured by 50% reduction in Sarkosyl-in
Falsification: Mice stratified by a single PTM marker (e.g., phospho-S396/S404 alone) show equivalent or superior therapeutic response to the combinatorial stratification group, indicating the combinatorial approach
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesis
| source | v1_phase_c_backfill |
| origin_type | debate_synthesis |
| _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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