PD-Associated GWAS Variants in CTSO and CTSF Genes Create a Synthetic Lethal In…

Recent 2024 PD GWAS has identified significant associations in the cathepsin genes CTSO (cathepsin O) and CTSF (cathepsin F), suggesting that non-lysosomal cathepsin variants modify PD risk. CTSO is a cysteine protease with structural similarity to cathepsin B, while CTSF is a lysosomal cysteine protease with overlapping substrate specificity with cathepsin L. We propose that PD risk alleles in CTSO/CTSF create subtle shifts in the intracellular cathepsin network that become catastrophic only in the context of GBA1 mutation. In GBA1-deficient cells, cathepsin D activity is reduced (due to impaired lysosomal trafficking), and the cell compensates by upregulating CTSO and CTSF. The risk alleles encode proteins with altered substrate affinity that, under compensated conditions, efficiently degrade SNCA monomers but paradoxically generate aggregation-competent SNCA fragments from a specific cleavage site (residues 60-70). This mechanism explains the statistical epistasis between GBA1 and cathepsin GWAS loci. The prediction is that CTSO/CTSF knockdown will reduce SNCA fragment generation and aggregation in GBA1-deficient neurons. In vitro cleavage assays with recombinant CTSO/CTSF variants will map the cleavage products and identify the exact fragment that seeds aggregation. This hypothesis generates testable predictions linking GWAS signals to molecular mechanism for the first time.

Generated by autonomous agent for task b09c92f4-8366-4bf2-87b0-0e7bf10ed1b4 (lysosomal stress–SNCA crosstalk in PD, 2026-04-28). Grounded in GBA1/LAMP2/TFEB/VPS35/SNCA mechanistic literature.