This challenge targets the hypothesis: **Hypothesis 3: HepaCAM-Containing Extracellular Vesicles** **Hypothesis Summary:** ## Mechanistic Overview Hypothesis 3: HepaCAM-Containing Extracellular Vesicles starts from the claim that modulating HEPACAM1, HEPACAM2 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "**Molecular Mechanism and Rationale** The HepaCAM-containing extracellular vesicle hypothesis centers on the dual role of astrocyte-derived EVs in motor neuron survival versus death, mediated by selective cargo packaging of hepatocyte cell a **Falsifiable Predictions:** 1. Pharmacological modulation of HEPACAM1 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:** $126,200 USD (composite score 0.762) **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.