Integrated stress response factors redirect transcription and chromatin regulation away from tau expression during acute proteotoxic stress.
Curated pathway from expert analysis
flowchart TD
A["MAPT/Tau Protein<br/>Microtubule Stabilizer"]
B["CDK5/GSK3B Activation<br/>Kinase Dysregulation"]
C["Tau Hyperphosphorylation<br/>Ser396/Thr231/Ser202"]
D["Tau Detachment<br/>Microtubule Destabilized"]
E["Tau Oligomers<br/>Paired Helical Filaments"]
F["Neurofibrillary Tangles<br/>Intraneuronal Inclusions"]
G["Axonal Transport Failure<br/>Synaptic Dysfunction"]
H["Neurodegeneration<br/>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:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for ATF4 yet. Search RCSB →
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 ATF4.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF SH‑SY5Y neuroblastoma cells are treated with the proteasome inhibitor bortezomib (200 nM) to induce acute proteostatic stress, THEN MAPT (tau) mRNA levels will decline significantly within 6 hours | At least a 30% reduction in MAPT transcript abundance as measured by qRT‑PCR. | — no observation — | pending | 0.70 |
| IF ATF4 and DDIT3 (CHOP) are knocked out using CRISPR/Cas9 in iPSC‑derived cortical neurons, THEN the previously observed repression of MAPT transcription during proteostatic stress (e.g., thapsigargi | MAPT mRNA levels in ATF4/DDIT3‑KO neurons will not differ significantly from untreated controls after 8 hours of thapsigargin (500 nM) stress. | — no observation — | pending | 0.65 |