This challenge targets the hypothesis: **eIF2α Phosphorylation Imbalance Creates Integrated Stress Response Overflow That Represses Axonal Protein Synthesis in ALS** **Hypothesis Summary:** The Integrated Stress Response (ISR) is a central regulatory pathway that controls global protein synthesis through phosphorylation of eIF2α (Ser51). In ALS motor neurons, this hypothesis proposes that chronic ISR activation (via PERK, GCN2, HRI, or PKR pathways) caused by proteostatic stress (TDP-43/FUS aggregates), oxidative stress, and ER stress creates a pathological eIF2α~P state that represses axonal protein synthesis below the threshold required for synaptic maintenance and axonal repair, **Falsifiable Predictions:** 1. Pharmacological modulation of the EIF2S1 pathway will alter neurodegeneration markers in validated ALS 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:** $136,600 USD (hypothesis-grade, composite score 0.866) **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.