Specific combinations of tau phosphorylation, acetylation, and truncation mark assemblies that evade degradation and template after synaptic transfer. Altering the PTM barcode should convert seed-competent tau into transferable but weakly pathogenic tau.
Curated pathway from expert analysis
flowchart TD A["MAPT tau protein"] -->|"phosphorylation, acetylation, truncation"| B["Combined PTM barcode"] C["CDK5, GSK3B kinases"] -->|"hyperphosphorylation"| A D["p300, CREBBP acetyltransferases"] -->|"acetylation"| A E["Caspases, Calpains"] -->|"truncation"| A B -->|"specific PTM pattern"| F["Seed-competent tau assemblies"] F -->|"resistant to clearance"| G["Evasion of proteostasis"] G -->|"enhanced stability"| F F -->|"packaged in vesicles"| H["Exosome release"] H -->|"intercellular transport"| I["Trans-synaptic transfer"] I -->|"propagation of misfolding"| J["Templating of native tau"] J -->|"spreading of pathology"| K["Neurodegeneration"] K -->|"neuronal loss"| L["Cognitive decline"] M["PTM barcode modification"] -.->|"restores degradability"| G M -.->|"reduces seed competency"| F N["Kinase inhibitors"] -->|"target upstream PTMs"| M O["Deacetylase activation"] -->|"alters acetylation marks"| M
No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for MAPT 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 MAPT.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.