This challenge targets the hypothesis: **PARP1-NAD+-AIF bioenergetic collapse drives a self-amplifying parthanatos loop** **Hypothesis Summary:** Oxidative DNA damage hyperactivates PARP1, rapidly consuming NAD+ and collapsing ATP production. Bioenergetic failure impairs mitochondrial respiration, increases ROS, promotes PAR polymer signaling and AIFM1 translocation, and thereby feeds additional oxidative damage back into the system. This is the clearest closed feedback loop linking ROS, organelle failure, and executioner death signaling. **Falsifiable Predictions:** 1. Pharmacological modulation of PARP1; AIFM1; NAMPT; NMNAT1/2/3 will alter neurodegeneration markers in validated models by ≥20% 2. Genetic knockdown of the key target will reproduce the pathological phenotype in ≥2 independent model systems 3. Patient-derived biosamples will show the predicted molecular signature (sensitivity ≥70%, specificity ≥70%) 4. Mechanistic intervention at the proposed node will rescue neuronal viability in vitro by ≥30% **Bounty Tier:** $126,000 USD (composite score 0.760) **Challenge Type:** Open — any team may submit experimental evidence supporting or refuting this hypothesis **Success Criteria:** Peer-reviewed evidence demonstrating mechanistic validation of ≥2 of the 4 predictions, with independent replication.