Impaired TFEB/TFE3 Nuclear Translocation Due to mTORC1 Hyperactivity in Motor Neurons
🧪 Overview
Motor neurons exhibit constitutive mTORC1 activation that phosphorylates TFEB/TFE3 transcription factors, sequestering them in the cytoplasm and preventing transcription of autophagy-lysosomal genes. This creates a 'locked' state where general autophagy inducers cannot overcome mTOR-mediated repression. However, SKEPTIC critique revealed this hypothesis may conflate upstream TFEB activation with downstream execution, and that constitutive mTORC1 activity reflects physiological neuronal homeostasis rather than dysregulation. DOMAIN_EXPERT recommends performing falsification experiment with constitutively nuclear TFEB before committing resources.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["Target Gene: mTORC1-TFEB/TFE3 axis CLEAR ge"]
B["Molecular Mechanism<br/>Pathway Activation"]
C["Cellular Phenotype<br/>Neuronal or Glial Response"]
D["Network Effect<br/>Circuit-Level Consequence"]
E["Disease Relevance<br/>Neurodegeneration Link"]
A --> B --> C --> D --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#1b5e20,stroke:#81c784,color:#81c784⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — MTORC1-TFEB
No curated PDB or AlphaFold mapping for MTORC1-TFEB yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for mTORC1-TFEB/TFE3 axis, CLEAR gene network from GTEx v10.
💉 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 mTORC1-TFEB.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
🔮 Predictions
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF we express constitutively nuclear TFEB (S211A mutant) in hiPSC-derived motor neurons with constitutive mTORC1 activation, THEN we expect significantly increased nuclear TFEB/TFE3 localization and e | Nuclear TFEB localization increases >3-fold; CLEAR gene network transcripts increase >2-fold relative to control | — no observation — | pending | 0.65 |
| IF we compare mTORC1 activity (p-S6K1 S389) and CLEAR gene network expression between motor neurons and other mTORC1-active neuronal populations (e.g., dopaminergic neurons from substantia nigra), THE | Motor neurons exhibit 40-60% lower CLEAR gene panel expression compared to dopaminergic neurons despite equivalent p-S6K1 levels | — no observation — | pending | 0.55 |
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |