Repeat-domain exposure defines seed-competent tau conformers
🧪 Overview
Tau assemblies become seed-competent when their repeat-domain surfaces adopt a conformation that both survives transfer and templates monomeric tau into pathological aggregates. This conformer-specific templating mechanism, supported by structural studies of disease-specific tau filaments, suggests that the exposed repeat domain interface is the critical determinant distinguishing pathogenic from non-pathogenic tau conformations. Non-pathogenic transferred tau lacks this exposed templating interface despite similar uptake, indicating that cellular internalization alone is insufficient for prion-like propagation. The probabilistic model of Alzheimer disease revised in 2022 suggests that such templated aggregation processes may be central to disease progression. Conformational exposure of the repeat domain thus defines seed-competent tau conformers and may represent a therapeutic target for preventing the establishment of the templating interface required for neurodegeneration.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD A["MAPT tau protein"] B["Repeat domain conformational change"] C["Exposed templating interface"] D["Seed-competent tau conformer"] E["Templating of monomeric tau"] F["Survival during intercellular transfer"] G["Non-pathogenic tau conformer"] H["Lacks exposed interface"] I["Propagation of tau aggregates"] J["Neurodegeneration"] A --> B B --> C C --> D C --> G D --> E D --> F E --> I F --> I I --> J G --> H H -.->|"No templating"| G
⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — MAPT
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for MAPT from GTEx v10.
💉 Clinical Trials (5)Relevance: 88%
Active
Completed
Total Enrolled
Highest Phase
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
📊 Market Indicators
💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |