NAD+ Precursor Supplementation to Reverse Poly(ADP-ribose) Polymerase-Driven Metabolic Catastrophe
Curated pathway from expert analysis
flowchart TD
A["DNA Single-Strand Breaks<br/>Oxidative Stress in AD"]
B["PARP1 Hyperactivation<br/>PAR Polymer Synthesis"]
C["NAD+ Depletion<br/>40-60% Loss in AD"]
D["SIRT1 Inactivation<br/>Deacetylase Impaired"]
E["PGC1alpha Inactivation<br/>Mitochondrial Biogenesis Loss"]
F["Energy Failure<br/>Neuronal Death"]
G["PARP1 Inhibitor<br/>Olaparib/Veliparib"]
A --> B
B --> C
C --> D
D --> E
E --> F
G -.->|"blocks"| B
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for PARP1, SIRT1/3, NAD+ 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 PARP1, SIRT1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF C57BL/6J mice with chronic low-dose doxorubicin-induced PARP1 activation (10 μg/kg/week for 8 weeks) receive oral nicotinamide riboside (NR) supplementation at 400 mg/kg/day for 8 weeks, THEN hepat | Hepatic NAD+ levels ≥2.5 nmol/mg protein, representing ≥50% restoration toward baseline | — no observation — | pending | 0.65 |
| IF NR supplementation (400 mg/kg/day for 8 weeks) is given to the same PARP1-hyperactive mice, THEN fasting blood glucose will decrease by ≥25% (to ≤140 mg/dL) and insulin sensitivity (assessed by HOM | Fasting blood glucose ≤140 mg/dL and HOMA-IR reduction of ≥30% | — no observation — | pending | 0.55 |