Recent PD GWAS identified associations in CTSO and CTSF alongside known GBA1 risk. The synthetic lethality hypothesis proposes that reduced non-lysosomal cathepsin activity in CTSO/CTSF carriers combined with GBA1-mediated glucocerebrosidase impairment creates a proteostatic crisis that accelerates α-synuclein aggregation beyond what either mutation alone causes. Testing this requires: (1) establishing the molecular mechanism (cathepsin B/D imbalance disrupting α-synuclein degradation), (2) demonstrating synergy (not additivity), and (3) identifying the intervention point. Falsifiable prediction: Combined CTSO siRNA + GBA1-N370S in dopaminergic neurons should increase α-synuclein seeding rate by ≥3× vs GBA1-N370S alone (Thioflavin T kinetics assay). CTSO knockout alone should increase seeding by <1.5×, establishing synergy above additivity. Recombinant cathepsin B supplementation should rescue the combined defect.