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

• Published in: Nature communications Vol. 14; no. 1; pp. 2174 - 11
• Main Authors: Fujii, Takuto, Nagamori, Shushi, Wiriyasermkul, Pattama, Zheng, Shizhou, Yago, Asaka, Shimizu, Takahiro, Tabuchi, Yoshiaki, Okumura, Tomoyuki, Fujii, Tsutomu, Takeshima, Hiroshi, Sakai, Hideki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.04.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/89; 14/1; 14/19; 38/22; 38/23; 38/70; 38/88; 38/89; 631/378/340; 631/45/56; 631/57/2283; 631/80; 82/16; 82/29; Accumulation; Acidification; Age; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Ca2+-transporting ATPase; Calcium (reticular); Calcium ions; Endoplasmic reticulum; H(+)-K(+)-Exchanging ATPase - genetics; H(+)-K(+)-Exchanging ATPase - metabolism; Humanities and Social Sciences; Humans; Hydrogen; Inhibitors; Lysosomes; Lysosomes - metabolism; Movement disorders; multidisciplinary; Mutation; Neurodegenerative diseases; Parkinson Disease - metabolism; Parkinson's disease; Pathogenesis; Pharmaceutical sciences; Polyamines; Potassium; Protein transport; Proton-Translocating ATPases - genetics; Proton-Translocating ATPases - metabolism; Science; Science (multidisciplinary); Statistical significance; Students; Synuclein; Thapsigargin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37815-z

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. Mutations in the human ATP13A2, a lysosomal ATPase, is associated with pathogenesis of Parkinson’s disease. Here, the authors show that ATP13A2 functions as H + /K + transporting protein, preventing lysosomal alkalinization and α-synuclein accumulation.