Solve: Repeat-domain exposure defines seed-competent tau conformers

Description

This challenge targets the hypothesis: **Repeat-domain exposure defines seed-competent tau conformers** **Hypothesis Summary:** Tau assemblies become seed-competent when their repeat-domain surfaces adopt a conformation that both survives transfer and templates monomeric tau into pathological aggregates. This conformer-specific templating mechanism, supported by structural studies of disease-specific tau filaments, suggests that the exposed repeat domain interface is the critical determinant distinguishing pathogenic from non-pathogenic tau conformations. Non-pathogenic transferred tau lacks this exposed templating inter **Falsifiable Predictions:** 1. Pharmacological modulation of MAPT 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.