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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Takuto Fujii & Shushi Nagamori & Pattama Wiriyasermkul & Shizhou Zheng & Asaka Yago & Takahiro Shimizu & Yoshiaki Tabuchi & Tomoyuki Okumura & Tsutomu Fujii & Hiroshi Takeshima & Hideki Sakai, 2023. "Parkinson’s disease-associated ATP13A2/PARK9 functions as a lysosomal H+,K+-ATPase," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37815-z
    DOI: 10.1038/s41467-023-37815-z
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    References listed on IDEAS

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