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PNPLA6 regulates retinal homeostasis by choline through phospholipid turnover

Author

Listed:
  • Takashi Ono

    (The University of Tokyo
    The University of Tokyo)

  • Yoshitaka Taketomi

    (The University of Tokyo)

  • Takayoshi Higashi

    (The University of Tokyo)

  • Hiroyasu Sato

    (The University of Tokyo)

  • Chika Mochizuki-Ono

    (The University of Tokyo)

  • Yuki Nagasaki

    (The University of Tokyo)

  • Takashi Ueta

    (The University of Tokyo)

  • Takashi Miyai

    (The University of Tokyo)

  • Suzumi M. Tokuoka

    (The University of Tokyo)

  • Yoshiya Oda

    (The University of Tokyo)

  • Yasumasa Nishito

    (Tokyo Metropolitan Institute of Medical Science)

  • Tomio Ono

    (Tokyo Metropolitan Institute of Medical Science)

  • Choji Taya

    (Tokyo Metropolitan Institute of Medical Science)

  • Satoru Arata

    (Showa University)

  • Sumiko Watanabe

    (The University of Tokyo)

  • Tomoyoshi Soga

    (Keio University)

  • Tetsuya Hirabayashi

    (Tokyo Metropolitan Institute of Medical Science)

  • Makoto Aihara

    (The University of Tokyo)

  • Makoto Murakami

    (The University of Tokyo
    Japan Agency for Medical Research and Development)

Abstract

Although mutations in human patatin-like phospholipase PNPLA6 are associated with hereditary retinal degenerative diseases, its mechanistic action in the retina is poorly understood. Here, we uncover the molecular mechanism by which PNPLA6 dysfunction disturbs retinal homeostasis and visual function. PNPLA6, by acting as a phospholipase B, regulates choline mobilization from phosphatidylcholine and subsequent choline turnover for phosphatidylcholine regeneration in retinal pigment epithelial cells. PNPLA6-driven choline is supplied from retinal pigment epithelial cells to adjacent photoreceptor cells to support their survival. Inhibition of this pathway results in abnormal morphology, proliferation, metabolism, and functions of retinal pigment epithelial and photoreceptor cells, and mice with retina-specific PNPLA6 deletion exhibit retinitis pigmentosa-like retinal degeneration. Notably, these abnormalities are entirely rescued by choline supplementation. Thus, PNPLA6 plays an essential role in retinal homeostasis by controlling choline availability for phospholipid recycling and provide a framework for the development of an ophthalmic drug target for retinal degeneration.

Suggested Citation

  • Takashi Ono & Yoshitaka Taketomi & Takayoshi Higashi & Hiroyasu Sato & Chika Mochizuki-Ono & Yuki Nagasaki & Takashi Ueta & Takashi Miyai & Suzumi M. Tokuoka & Yoshiya Oda & Yasumasa Nishito & Tomio O, 2025. "PNPLA6 regulates retinal homeostasis by choline through phospholipid turnover," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57402-8
    DOI: 10.1038/s41467-025-57402-8
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    References listed on IDEAS

    as
    1. Rosemary J. Cater & Dibyanti Mukherjee & Eva Gil-Iturbe & Satchal K. Erramilli & Ting Chen & Katie Koo & Nicolás Santander & Andrew Reckers & Brian Kloss & Tomasz Gawda & Brendon C. Choy & Zhening Zha, 2024. "Structural and molecular basis of choline uptake into the brain by FLVCR2," Nature, Nature, vol. 629(8012), pages 704-709, May.
    2. S. Kmoch & J. Majewski & V. Ramamurthy & S. Cao & S. Fahiminiya & H. Ren & I. M. MacDonald & I. Lopez & V. Sun & V. Keser & A. Khan & V. Stránecký & H. Hartmannová & A. Přistoupilová & K. Hodaňová & L, 2015. "Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness," Nature Communications, Nature, vol. 6(1), pages 1-10, May.
    3. Mahtab Tavasoli & Sarah Lahire & Stanislav Sokolenko & Robyn Novorolsky & Sarah Anne Reid & Abir Lefsay & Meredith O. C. Otley & Kitipong Uaesoontrachoon & Joyce Rowsell & Sadish Srinivassane & Molly , 2022. "Mechanism of action and therapeutic route for a muscular dystrophy caused by a genetic defect in lipid metabolism," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. Yeeun Son & Timothy C. Kenny & Artem Khan & Kıvanç Birsoy & Richard K. Hite, 2024. "Structural basis of lipid head group entry to the Kennedy pathway by FLVCR1," Nature, Nature, vol. 629(8012), pages 710-716, May.
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