PNPLA6 regulates retinal homeostasis by choline through phospholipid turnover
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.
Authors
- Sumiko Watanabe (ORCID: https://orcid.org/0000-0003-4497-5750)
- Choji Taya
- Takashi Miyai (ORCID: https://orcid.org/0000-0001-5286-8272)
- Tetsuya Hirabayashi (ORCID: https://orcid.org/0000-0001-8099-5367)
- Tomoyoshi Soga (ORCID: https://orcid.org/0000-0001-9502-2509)
- Yuki Nagasaki (ORCID: https://orcid.org/0000-0002-4717-6877)
- Takashi Ono (ORCID: https://orcid.org/0000-0002-1288-2798)
- Makoto Aihara (ORCID: https://orcid.org/0000-0001-6810-0583)
- Takashi Ueta (ORCID: https://orcid.org/0000-0001-5995-7438)
- Yasumasa Nishito (ORCID: https://orcid.org/0000-0001-7621-6172)
- Suzumi M. Tokuoka (ORCID: https://orcid.org/0009-0000-3600-3236)
- Makoto Murakami (ORCID: https://orcid.org/0000-0002-4565-6017)
- Yoshiya Oda
- Satoru Arata
- Takayoshi Higashi (ORCID: https://orcid.org/0000-0002-5262-091X)
- Hiroyasu Sato (ORCID: https://orcid.org/0000-0002-9566-834X)
- Yoshitaka Taketomi (ORCID: https://orcid.org/0000-0003-4094-9846)
- Tomio Ono
- Chika Mochizuki-Ono
Institutions
- SHOWA Medical University (JP)
- Keio University (JP)
- Japan Agency for Medical Research and Development (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-13
- DOI
- https://doi.org/10.1038/s41467-025-57402-8
- Citations
- 5
- Primary Topic
- Retinal Diseases and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 8.54
Funders
- Takeda Science Foundation
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science