Parkinson's disease-associated ATP13A2/PARK9 functions as a lysosomal H,K-ATPase.

Mutations in the human ATP13A2 (PARK9), a lysosomal ATPase, cause Kufor-Rakeb Syndrome, an early-onset form of Parkinson's disease (PD). Here, we demonstrate that ATP13A2 functions as a lysosomal H,K-ATPase. The K-dependent ATPase activity and the lysosomal K-transport activity of ATP13A2 are inhibited by an inhibitor of sarco/endoplasmic reticulum Ca-ATPase, thapsigargin, and K-competitive inhibitors of gastric H,K-ATPase, such as vonoprazan and SCH28080. Interestingly, these H,K-ATPase inhibitors cause lysosomal alkalinization and α-synuclein accumulation, which are pathological hallmarks of PD. Furthermore, PD-associated mutants of ATP13A2 show abnormal expression and function. Our results suggest that the H/K-transporting function of ATP13A2 contributes to acidification and α-synuclein degradation in lysosomes.