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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 ATP13A...

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Detalles Bibliográficos
Autores principales: Fujii, Takuto, Nagamori, Shushi, Wiriyasermkul, Pattama, Zheng, Shizhou, Yago, Asaka, Shimizu, Takahiro, Tabuchi, Yoshiaki, Okumura, Tomoyuki, Fujii, Tsutomu, Takeshima, Hiroshi, Sakai, Hideki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10119128/
https://www.ncbi.nlm.nih.gov/pubmed/37080960
http://dx.doi.org/10.1038/s41467-023-37815-z
Descripción
Sumario: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.