TFEB (together with TFE3 and TFEB family members) is a master transcriptional regulator of lysosomal biogenesis and autophagy. In aged synapses, lysosomal degradation is often impaired, a defect reflected by autophagosome accumulation despite intact initiation (PMID:30401736). In Alzheimer’s disease (AD) brain tissue, mTOR hyperactivation prevents TFEB nuclear translocation, limiting lysosomal gene expression (PMID:29079772). Pharmacologic inhibition of mTOR with rapamycin analogs or direct overexpression of TFEB can promote nuclear TFEB localization and has been shown to reduce tau aggregation and Aβ toxicity in cellular models (PMID:25661182). Moreover, TFEB activation can bypass upstream mTOR dysregulation and directly drive expression of lysosomal hydrolases and membrane proteins (PMID:31835980). However, TFEB governs a broad transcriptional network that includes lipid metabolism and inflammatory pathways (PMID:28628114), and global or neuron‑non‑specific overexpression can exacerbate neurodegeneration in α‑synuclein models via APP‑like substrate processing (PMID:31225475).
...Curated pathway from expert analysis
flowchart TD
A["mTORC1 Hyperactivation<br/>Nutrient/Growth Signals"]
B["TFEB Phosphorylation<br/>Ser211 by mTORC1"]
C["14-3-3 Sequestration<br/>Cytoplasmic Retention"]
D["Lysosomal Biogenesis<br/>Blocked"]
E["Autophagic Flux<br/>Impaired"]
F["Tau/Amyloid Aggregate<br/>Accumulation"]
G["TFEB Activation<br/>Rapamycin or MCOLN1"]
H["Nuclear TFEB<br/>CLEAR Gene Expression"]
G --> H
H -.->|"rescues"| D
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style H fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for TFEB yet. Search RCSB →
Median TPM across 13 brain regions for TFEB (TFE3, TFE4 family) from GTEx v10.
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 TFEB (TFE3, TFE4 family).
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF pharmacologically activate TFEB using a selective agonist (e.g., trehalose or novel synthetic activator) in primary hippocampal neurons cultured from aged (18-24 month) C57BL/6 mice, THEN lysosomal | Increased lysosomal biogenesis and synaptic protein levels in aged neurons following TFEB activation | — no observation — | pending | 0.58 |
| IF genetically overexpress TFEB via AAV9-mediated delivery in the hippocampus of aged (20-22 month) C57BL/6 mice, THEN lysosomal proteostasis markers (LC3-II/LC3-I ratio, Cathepsin D levels) will norm | Restoration of lysosomal proteostasis and improvement in spatial memory performance following TFEB overexpression in aged mice | — no observation — | pending | 0.52 |