This challenge targets the hypothesis: **GLE1-Mediated mRNA Export Defect Creates Translation-Competent mRNA Starvation in ALS Motor Neuron Axons** **Hypothesis Summary:** GLE1 (Gle1) is an essential mRNA export factor that functions at the nuclear pore complex (NPC) cytoplasmic face, mediating the release of mRNA export complexes into the cytoplasm. This hypothesis proposes that ALS-linked GLE1 mutations (p.R392X, p.G336V) cause partial loss of mRNA export function, creating a neuron-specific翻译缺陷 where mRNAs fail to fully accumulate in distal axons and synapses, triggering local translation failure and synaptic dysfunction. The mechanistic prediction is that moto **Falsifiable Predictions:** 1. Pharmacological modulation of the GLE1 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:** $132,600 USD (hypothesis-grade, composite score 0.826) **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.