This challenge targets the hypothesis: **TBK1-OPTN-NDP52 Phospho-Cascade Coordinates Multi-Organelle Autophagy** **Hypothesis Summary:** ## Mechanistic Overview TBK1-OPTN-NDP52 Phospho-Cascade Coordinates Multi-Organelle Autophagy starts from the claim that modulating TBK1, OPTN (TBC1D7), NDP52/CALCOCO2 within the disease context of neurodegeneration can redirect a disease-relevant process. The original description reads: "**Molecular Mechanism and Rationale** The TBK1-OPTN-NDP52 phospho-cascade represents a sophisticated cellular quality control network that orchestrates selective autophagy across multiple organellar compartment **Falsifiable Predictions:** 1. Pharmacological modulation of TBK1 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:** $127,200 USD (composite score 0.772) **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.