This challenge targets the hypothesis: **SFPQ Paralog Displacement Triggers Cryptic Polyadenylation and Global RNA Stability Loss in ALS Motor Neurons** **Hypothesis Summary:** SFPQ (Splicing Factor Proline-Glutamine Rich) is a non-POU domain octamer binding protein (NONO) family member that functions as an essential splicing factor and RNA processing scaffold. This hypothesis proposes that in ALS motor neurons, TDP-43 cytoplasmic mislocalization causes partial depletion of nuclear SFPQ from its normal genomic loci, triggering expression of a set of germline-era SFPQ-paralog (PSP1/NONO) genes normally silenced in differentiated neurons. These paralogs compete with SFPQ **Falsifiable Predictions:** 1. Pharmacological modulation of the SFPQ 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:** $135,000 USD (hypothesis-grade, composite score 0.850) **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.