This challenge targets the hypothesis: **TIA1 Low-Complexity Domain Oxidation Drives Aberrant Stress Granule Assembly and TDP-43 Mislocalization in ALS Motor Neurons** **Hypothesis Summary:** TIA1 (TIA-1) is an essential stress granule (SG) nucleator that undergoes oxidation-sensitive conformational changes in its low-complexity (LC) domain, modulating SG assembly dynamics. This hypothesis proposes that in ALS motor neurons, chronic oxidative stress (elevated ROS, mitochondrial dysfunction) causes irreversible oxidation of TIA1's LC domain cysteines, locking TIA1 into a hyper-assembly state that nucleates aberrant, gel-like SGs with altered material properties. These oxidized TIA1-SG **Falsifiable Predictions:** 1. Pharmacological modulation of the TIA1 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:** $131,000 USD (hypothesis-grade, composite score 0.810) **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.