Dichloroacetate-mediated PDH activation redirects pyruvate into TCA cycle, reducing NADPH and acetyl-CoA substrate supply for de novo lipogenesis. Metabolic correction approach that bypasses direct AMPK targeting. Weak CNS pharmacology and non-neuron-specific effects limit utility; requires neuron-specific validation.
Curated pathway from expert analysis
flowchart TD A["AMPK alpha Complex<br/>PRKAA1/PRKAA2 Energy Sensor"] B["ATP Stress Detection<br/>AMP-to-ATP Ratio Shift"] C["ULK1 and Autophagy Activation<br/>Cellular Recovery Program"] D["mTORC1 Restraint<br/>Anabolic Pressure Reduced"] E["Inflammation Resolution Support<br/>Metabolic Rebalancing"] F["Post-onset Neuronal Rescue<br/>Reversibility Test Readout"] A --> B B --> C B --> D C --> E D --> E E --> F style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7 style E fill:#1b5e20,stroke:#81c784,color:#81c784 style F fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for PDHA1 yet. Search RCSB →
Median TPM across 13 brain regions for PDHA1 (Pyruvate dehydrogenase α1) 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 PDHA1 (Pyruvate dehydrogenase α1).
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF PDH is activated by dichloroacetate in neurons (≥0.5 mM), THEN intracellular NADPH and acetyl-CoA pools will be reduced (depleting lipogenesis substrates), measurable via targeted metabolomics, wit | ≥25% decrease in NADPH levels and ≥30% reduction in acetyl-CoA concentration relative to vehicle controls, with reciprocal ≥50% increase in TCA cycle intermedia | — no observation — | pending | 0.48 |
| IF primary cortical neurons or iPSC-derived dopaminergic neurons are treated with dichloroacetate at concentrations ≥0.5 mM (achieving PDH activation), THEN de novo lipogenesis will be suppressed, as | ≥40% reduction in lipid synthesis rate (14C-acetate incorporation) and ≥30% decrease in FASN (fatty acid synthase) protein expression relative to vehicle-treate | — no observation — | pending | 0.55 |