Challenge generated from hypothesis h-f32ba823 (composite_score=0.798). Target gene/pathway: MANF, CDNF. Source hypothesis: Hypothesis 1: MANF/CDNF Signaling as Primary Neuroprotective Effector. ## Falsifiable Predictions 1. Recombinant MANF (1-10 μg/mL) reduces ER stress markers (ATF4, CHOP, GRP78) by >40% in tunicamycin-stressed SH-SY5Y cells. 2. AAV-MANF or AAV-CDNF delivery maintains TH+ dopaminergic neuron counts at >80% of sham levels (vs <50% in AAV-GFP controls) in 6-OHDA unilateral striatal lesion model. 3. CSF MANF protein positively correlates (r > 0.5, p < 0.01) with dopaminergic neuron viability in post-mortem PD brain cohort (n >= 30). 4. MANF-KO mice show >30% increase in nigral dopaminergic neuron loss after mild 6-OHDA challenge vs WT, confirming endogenous necessity.