This challenge targets the hypothesis: **Exposed amyloidogenic segments (β-sheet propensity residues) serve as HSP70 recognition codes** **Hypothesis Summary:** ## **Molecular Mechanism and Rationale** The recognition of amyloidogenic protein species by the heat shock protein 70 (HSP70) chaperone network represents a sophisticated quality control mechanism that distinguishes pathological conformers from their native counterparts through the exposure of specific β-sheet propensity sequences. This molecular recognition system centers on the constitutive HSP70 isoforms HSPA8 (also known as HSC70) and the inducible HSPA1A, which function in concert with th **Falsifiable Predictions:** 1. Pharmacological modulation of the HSPA8 pathway will alter neurodegeneration markers in validated protein biochemistry models by ≥20% relative to controls 2. Genetic knockdown of the key molecular target will reproduce the proposed pathological phenotype in ≥2 independent model systems 3. Patient-derived biosamples will show the predicted molecular signature with sensitivity ≥70% and specificity ≥70% vs healthy controls 4. Therapeutic intervention at the proposed mechanistic node will rescue neuronal viability in vitro by ≥30% **Bounty Tier:** $129,004 USD (hypothesis-grade, composite score 0.790) **Challenge Type:** Open — any team may submit experimental evidence **Success Criteria:** Peer-reviewed publication or preprint with independent replication demonstrating mechanistic validation of ≥2 of the 4 predictions above.