This challenge targets the hypothesis: **ATM Kinase Hyperactivation Triggers DNA Damage Response Overflow and p53-Dependent Motor Neuron Apoptosis in ALS** **Hypothesis Summary:** ATM (Ataxia Telangiectasia Mutated) is a DNA damage response (DDR) kinase that normally activates in response to double-strand breaks (DSBs). This hypothesis proposes that in ALS, chronic mitochondrial dysfunction and ROS overproduction cause persistent low-level ATM activation that exceeds the capacity of DNA repair machinery, leading to DDR overflow and pathological p53 activation that drives motor neuron apoptosis. The mechanistic prediction is that in ALS motor neurons, elevated mtROS causes **Falsifiable Predictions:** 1. Pharmacological modulation of the ATM 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:** $134,200 USD (hypothesis-grade, composite score 0.842) **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.