Constitutive ULK1 activation via AAV-hSyn-ULK1(S317A) enhances lipophagy to sequester excess neuronal lipids into lysosomes for degradation. Addresses the metabolic routing defect underlying lipid droplet accumulation and unconventional secretion. Mechanistically compelling but construct validation and lipophagy specificity remain concerns.
Curated pathway from expert analysis
flowchart TD
A["mTORC1 Off / AMPK On<br/>Energy/Nutrient Deficit"]
B["ULK1-ATG13-FIP200<br/>Initiation Complex Assembly"]
C["ULK1 Autophosphorylation<br/>Ser317/Ser777 by AMPK"]
D["VPS34/BECN1 PI3K<br/>PI3P Generation on ER"]
E["DFCP1/WIPI2 Recruitment<br/>Omegasome Formation"]
F["ATG12-ATG5-ATG16L1<br/>LC3-II Lipidation"]
G["Autophagosome Maturation<br/>Cargo Capture and Fusion"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style G fill:#1b5e20,stroke:#81c784,color:#81c784No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for ULK1 (autophagy initiation kinase) 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 ULK1 (autophagy initiation kinase).
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF AAV-hSyn-ULK1(S317A) is expressed in primary cortical neurons derived from N171-82Q mice, THEN lysosomal fraction cholesteryl ester and ceramide content will increase by at least 35% while total ce | Increased lipid routing to lysosomes (elevated lysosomal cholesteryl esters/ceramides) with concurrent reduction in cytosolic lipid droplets | — no observation — | pending | 0.45 |
| IF AAV-hSyn-ULK1(S317A) (constitutive ULK1 activation) is stereotaxically injected into the striatum of 8-week-old N171-82Q Huntington disease mice (model of neuronal lipid droplet accumulation), THEN | Significant reduction in neuronal lipid droplet burden with ULK1(S317A) expression | — no observation — | pending | 0.55 |