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

Takuto Fujii (), Shushi Nagamori, Pattama Wiriyasermkul, Shizhou Zheng, Asaka Yago, Takahiro Shimizu, Yoshiaki Tabuchi, Tomoyuki Okumura, Tsutomu Fujii, Hiroshi Takeshima and Hideki Sakai ()
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Takuto Fujii: University of Toyama
Shushi Nagamori: The Jikei University School of Medicine
Pattama Wiriyasermkul: The Jikei University School of Medicine
Shizhou Zheng: University of Toyama
Asaka Yago: University of Toyama
Takahiro Shimizu: University of Toyama
Yoshiaki Tabuchi: University of Toyama
Tomoyuki Okumura: University of Toyama
Tsutomu Fujii: University of Toyama
Hiroshi Takeshima: Kyoto University
Hideki Sakai: University of Toyama

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract 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 Ca2+-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.

Date: 2023
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DOI: 10.1038/s41467-023-37815-z

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