{"ranked_hypotheses":[{"rank":1,"title":"AMPK-ULK1 Autophagy Dysregulation","mechanism":"MCT1 disruption reduces axonal lactate transport, depleting ATP and suppressing AMPK activity below threshold, preventing ULK1 phosphorylation at Ser555 and blocking autophagosome formation, causing damaged mitochondria accumulation.","target_gene":"MCT1 (SLC16A1)","confidence_score":0.55,"novelty_score":0.7,"feasibility_score":0.45,"impact_score":0.75,"composite_score":0.63,"testable_prediction":"Measure axonal AMPK activity and ULK1 Ser555 phosphorylation in MCT1 cKO mice at pre-degeneration timepoints using phospho-specific immunostaining.","skeptic_concern":"Causal chain from lactate transport to AMPK activation in distal axons remains unverified; distal axonal compartments may have heterogenous metabolic regulation."},{"rank":2,"title":"NAD+ Regeneration Failure and Sirtuin Dysfunction","mechanism":"Oligodendrocyte-derived lactate supports axonal NAD+ regeneration; MCT1 loss impairs NAD+ biosynthesis, reducing sirtuin activity and compromising mitochondrial quality control and DNA repair.","target_gene":"MCT1 (SLC16A1)","confidence_score":0.6,"novelty_score":0.55,"feasibility_score":0.55,"impact_score":0.7,"composite_score":0.61,"testable_prediction":"Measure axonal NAD+/NADH ratios and SIRT1 activity in MCT1-deficient neurons using fluorescent biosensors before degeneration onset.","skeptic_concern":"NAD+ depletion is downstream of multiple pathways; direct evidence linking lactate transport to axonal NAD+ levels is lacking."},{"rank":3,"title":"Axonal Calcium Dysregulation via Energy Depletion","mechanism":"Lactate deprivation from MCT1 loss causes axonal ATP depletion, impairing calcium ATPase (PMCA) and Na+/Ca2+ exchanger function, leading to calcium accumulation and activation of calcium-dependent proteases (calpains).","target_gene":"MCT1 (SLC16A1)","confidence_score":0.5,"novelty_score":0.5,"feasibility_score":0.6,"impact_score":0.65,"composite_score":0.55,"testable_prediction":"Use GCaMP imaging in live MCT1-deficient axons to monitor calcium dynamics during lactate withdrawal.","skeptic_concern":"Calcium dysregulation may be a secondary effect rather than primary driver; temporal ordering relative to other pathways unclear."}],"consensus_points":["MCT1-mediated lactate transport from oligodendrocytes is essential for axonal metabolic support.","Axonal degeneration in MCT1 deficiency exhibits a dying-back pattern preceding somatic involvement.","Distal axons are particularly vulnerable to metabolic compromise due to their compartment-specific energy requirements."],"dissent_points":["Whether AMPK is the primary sensor linking lactate availability to autophagy regulation in axons remains contested; alternative energy sensors or direct mechanisms may predominate."],"debate_summary":"The debate centers on whether the primary mechanism linking MCT1 disruption to axonal degeneration operates through AMPK-ULK1 autophagy failure, NAD+-dependent sirtuin dysfunction, or calcium dysregulation secondary to energy depletion. While all hypotheses recognize metabolic support failure as central, they differ on which downstream pathway is rate-limiting. The unverified causal chain from lactate transport to AMPK activation remains the critical gap, making direct axonal measurements essential for testing these competing models."}