This challenge targets the hypothesis: **MATR3 Nuclear Body Disruption Impairs RNA Processing Hubs and Triggers Splicing Defects in ALS Motor Neurons** **Hypothesis Summary:** MATR3 (Matrin-3) is a nuclear matrix protein that forms distinct nuclear bodies (MATR3-NBs) functioning as RNA processing hubs for spliceosome recycling and transcription termination. This hypothesis proposes that ALS-linked MATR3 mutations (p.S85C, p.F115C, p.G497E) disrupt MATR3-NB integrity, causing aberrant spliceosome dynamics, intron retention accumulation, and nuclear RNA export defects that trigger motor neuron death. The mechanistic prediction is that MATR3-NBs serve as transient storag **Falsifiable Predictions:** 1. Pharmacological modulation of the MATR3 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:** $131,800 USD (hypothesis-grade, composite score 0.818) **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.