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(2+)-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.