A broader neuronal downscaling program contributes to tau repression when stress becomes chronic or severe.
Curated pathway from expert analysis
flowchart TD
A["REST/NRSF Transcriptional Repressor<br/>Neuronal Gene Silencing Factor"]
B["GABAergic and Synaptic Gene Suppression<br/>Non-neuronal Cell Identity Maintenance"]
C["Tau and ATXN2 Modulation<br/>Neurodegeneration Linkage"]
D["REST Deficiency in Aging<br/>Neurotoxic Gene Derepression"]
E["Neuronal Identity Loss<br/>Synaptic Vulnerability"]
F["REST Activating Compounds<br/>Neuroprotective Target Validation"]
G["AD and FTD Mechanisms<br/>REST-Dependent Protection Failure"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for REST 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 REST.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF REST is knocked down via shRNA in primary mouse cortical neurons prior to proteasome inhibition (lactacystin, 5 µM), THEN tau protein levels will remain elevated (no suppression) and neurons will s | Control shRNA neurons: MAPT mRNA decreases 45% and tau protein decreases 35%; REST shRNA neurons: MAPT mRNA decreases <10% and tau protein remains at baseline o | — no observation — | pending | 0.58 |
| IF human iPSC-derived cortical neurons are treated with proteasome inhibitor (MG-132, 1 µM) for 48 hours to induce severe proteostatic stress, THEN REST mRNA and protein levels will increase by >2-fol | REST protein levels increase 2.2-3.0 fold; MAPT mRNA decreases 40-60% (qPCR) and soluble tau protein decreases 30-50% (ELISA) relative to vehicle controls | — no observation — | pending | 0.65 |