IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-37815-z.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-37815-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-37815-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Rong Wang & Jin Wang & Abdirahman Hassan & Chia-Hsueh Lee & Xiao-Song Xie & Xiaochun Li, 2021. "Molecular basis of V-ATPase inhibition by bafilomycin A1," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    2. Jinhong Wie & Zhenjiang Liu & Haikun Song & Thomas F. Tropea & Lu Yang & Huanhuan Wang & Yuling Liang & Chunlei Cang & Kimberly Aranda & Joey Lohmann & Jing Yang & Boxun Lu & Alice S. Chen-Plotkin & K, 2021. "Author Correction: A growth-factor-activated lysosomal K+ channel regulates Parkinson’s pathology," Nature, Nature, vol. 592(7855), pages 10-10, April.
    3. Ping Li & Kaituo Wang & Nina Salustros & Christina Grønberg & Pontus Gourdon, 2021. "Structure and transport mechanism of P5B-ATPases," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    4. Jinhong Wie & Zhenjiang Liu & Haikun Song & Thomas F. Tropea & Lu Yang & Huanhuan Wang & Yuling Liang & Chunlei Cang & Kimberly Aranda & Joey Lohmann & Jing Yang & Boxun Lu & Alice S. Chen-Plotkin & K, 2021. "A growth-factor-activated lysosomal K+ channel regulates Parkinson’s pathology," Nature, Nature, vol. 591(7850), pages 431-437, March.
    5. Kazuhiro Abe & Katsumasa Irie & Hanayo Nakanishi & Hiroshi Suzuki & Yoshinori Fujiyoshi, 2018. "Crystal structures of the gastric proton pump," Nature, Nature, vol. 556(7700), pages 214-218, April.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Youyou Lu & Xuan Zhang & Liyan Zhao & Hong Liu & Mi Yan & Xiaochen Zhang & Kenji Mochizuki & Shikuan Yang, 2023. "Metal-organic framework template-guided electrochemical lithography on substrates for SERS sensing applications," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Shihao Su & Yifan Zhang & Shengyuan Peng & Linxin Guo & Yong Liu & Engang Fu & Huijun Yao & Jinlong Du & Guanghua Du & Jianming Xue, 2022. "Multifunctional graphene heterogeneous nanochannel with voltage-tunable ion selectivity," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Phong T. Nguyen & Christine Deisl & Michael Fine & Trevor S. Tippetts & Emiko Uchikawa & Xiao-chen Bai & Beth Levine, 2022. "Structural basis for gating mechanism of the human sodium-potassium pump," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Wu, Yaobin & Huang, Jiazhou & Chen, Xiangfeng, 2024. "The information value of logistics platforms in a freight matching market," European Journal of Operational Research, Elsevier, vol. 312(1), pages 227-239.
    5. Victoria C. Young & Hanayo Nakanishi & Dylan J. Meyer & Tomohiro Nishizawa & Atsunori Oshima & Pablo Artigas & Kazuhiro Abe, 2022. "Structure and function of H+/K+ pump mutants reveal Na+/K+ pump mechanisms," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Ping Li & Amber L. Hendricks & Yong Wang & Rhiza Lyne E. Villones & Karin Lindkvist-Petersson & Gabriele Meloni & J. A. Cowan & Kaituo Wang & Pontus Gourdon, 2022. "Structures of Atm1 provide insight into [2Fe-2S] cluster export from mitochondria," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    7. Rong Wang & Yu Qin & Xiao-Song Xie & Xiaochun Li, 2022. "Molecular basis of mEAK7-mediated human V-ATPase regulation," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    8. Zongxin Guo & Fredrik Orädd & Viktoria Bågenholm & Christina Grønberg & Jian Feng Ma & Peter Ott & Yong Wang & Magnus Andersson & Per Amstrup Pedersen & Kaituo Wang & Pontus Gourdon, 2024. "Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Jianqiang Mu & Chenyang Xue & Lei Fu & Zongjun Yu & Minhan Nie & Mengqi Wu & Xinmeng Chen & Kun Liu & Ruiqian Bu & Ying Huang & Baisheng Yang & Jianming Han & Qianru Jiang & Kevin C. Chan & Ruhong Zho, 2023. "Conformational cycle of human polyamine transporter ATP13A2," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37815-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.