This challenge targets the hypothesis: **Exosomal SNCA Propagation from Lysosome-Compromised Neurons Contains a Distinct Lysosomal Proteome Signature that Primes Recipient Cells for Aggregation** **Hypothesis Summary:** Dopaminergic neurons with lysosomal stress (either from GBA1 mutations, VPS35 dysfunction, or age-related LAMP2A decline) release exosomes enriched in SNCA via a mechanism involving CD63 and syntenin-mediated exosome biogenesis at multivesicular bodies (MVBs). Critically, these exosomes carry a distinct cargo signature reflecting their lysosomal origin: they are enriched in mature cathepsins (particularly cathepsin D in its active form), LAMP1 fragments, and glucosylceramide. When these exosomes **Falsifiable Predictions:** 1. Pharmacological modulation of SNCA 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:** $127,670 USD (composite score 0.777) **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.