This challenge targets the hypothesis: **cGAS-STING Pathway Hyperactivation Mediates Tau Propagation** **Hypothesis Summary:** **Molecular Mechanism and Rationale** The cGAS-STING (cyclic GMP-AMP synthase - stimulator of interferon genes) pathway represents a fundamental innate immune sensing mechanism that detects cytosolic double-stranded DNA (dsDNA) and initiates inflammatory responses. In the context of tauopathies, hyperphosphorylated tau protein disrupts mitochondrial integrity through multiple mechanisms, leading to mitochondrial DNA (mtDNA) release into the cytoplasm where it acts as a damage-associated molecul **Falsifiable Predictions:** 1. Pharmacological modulation of cGAS (CGAS) 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.