2. Academic Validation
  3. PNPLA6 regulates retinal homeostasis by choline through phospholipid turnover

PNPLA6 regulates retinal homeostasis by choline through phospholipid turnover

  • Nat Commun. 2025 Mar 13;16(1):2221. doi: 10.1038/s41467-025-57402-8.
Takashi Ono 1 2,  Yoshitaka Taketomi 1,  Takayoshi Higashi 1,  Hiroyasu Sato 1,  Chika Mochizuki-Ono 1,  Yuki Nagasaki 1,  Takashi Ueta 2,  Takashi Miyai 2,  Suzumi M Tokuoka 3,  Yoshiya Oda 3,  Yasumasa Nishito 4,  Tomio Ono 4,  Choji Taya 4,  Satoru Arata 5,  Sumiko Watanabe 6,  Tomoyoshi Soga 7,  Tetsuya Hirabayashi 8,  Makoto Aihara 2,  Makoto Murakami 9 10
Affiliations

Affiliations

  • 1 Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • 2 Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • 3 Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • 4 Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.
  • 5 Faculty of Arts and Sciences at Fujiyoshida, Showa University, Fuji-yoshida-shi, Yamanashi, Japan.
  • 6 Department of Retinal Biology and Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • 7 Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
  • 8 Biomembrane group, Technology Research Division, Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.
  • 9 Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. makmurak@m.u-tokyo.ac.jp.
  • 10 AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda City, Tokyo, Japan. makmurak@m.u-tokyo.ac.jp.
PMID: 40082403 DOI: 10.1038/s41467-025-57402-8
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.

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Products
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  • HY-108431
    99.72%, CHKα Inhibitor