PNPLA6 regulates retinal homeostasis by choline through phospholipid turnover

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 Ono, Choji Taya, Satoru Arata, Sumiko Watanabe, Tomoyoshi Soga, Tetsuya Hirabayashi, Makoto Aihara and Makoto Murakami ()
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Takashi Ono: 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

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57402-8

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