This challenge targets the hypothesis: **hnRNP A2/B1 Staufen2-Mediated Axonal RNA Granule Transport Failure Drives Distal Axon Degeneration in ALS** **Hypothesis Summary:** hnRNP A2/B1 is an RNA-binding protein that assembles into axonal RNA granules with Staufen2 (STAU2), mediating the long-range transport of mRNAs (including β-actin, Arp2/3, MAP1B) along microtubules in motor neuron axons. This hypothesis proposes that ALS-linked hnRNP A2/B1 dysfunction (mutations p.P193L, post-translational modification changes) disrupts axonal RNA granule transport, creating a dual defect: (1) insufficient delivery of structural and synaptic protein mRNAs to distal axons, and ( **Falsifiable Predictions:** 1. Pharmacological modulation of the HNRNPA2B1 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:** $133,400 USD (hypothesis-grade, composite score 0.834) **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.