期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 15, 页码 3936-3941出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1717338115
关键词
Bietti's crystalline dystrophy; cholesterol; CYP4V2 gene; induced pluripotent stem cells; retinal pigment epithelium
资金
- Ono Medical Research Foundation
- Novartis Pharma
- Takeda Science Foundation
- Japan National Society for the Prevention of Blindness
- Japan Society for the Promotion of Science [JP16H01359, JP16 K11285, JP15H05897, 15H05898, 15H04648]
- Translational Research Network Program of the Japan Agency for Medical Research and Development (AMED)
- AMED Program for Intractable Diseases Research Utilizing Disease-Specific iPS cells [15652070]
- [15K20255]
- [17K16967]
- Grants-in-Aid for Scientific Research [16K11285, 17K16967, 16H01359, 16K20316, 15H04648, 15H05898] Funding Source: KAKEN
Bietti's crystalline dystrophy (BCD) is an intractable and progressive chorioretinal degenerative disease caused by mutations in the CYP4V2 gene, resulting in blindness in most patients. Although we and others have shown that retinal pigment epithelium (RPE) cells are primarily impaired in patients with BCD, the underlying mechanisms of RPE cell damage are still unclear because we lack access to appropriate disease models and to lesion-affected cells from patients with BCD. Here, we generated human RPE cells from induced pluripotent stem cells (iPSCs) derived from patients with BCD carrying a CYP4V2 mutation and successfully established an in vitro model of BCD, i.e., BCD patient-specific iPSC-RPE cells. In this model, RPE cells showed degenerative changes of vacuolated cytoplasm similar to those in postmortem specimens from patients with BCD. BCD iPSC-RPE cells exhibited lysosomal dysfunction and impairment of autophagy flux, followed by cell death. Lipidomic analyses revealed the accumulation of glucosylceramide and free cholesterol in BCD-affected cells. Notably, we found that reducing free cholesterol by cyclodextrins or delta-tocopherol in RPE cells rescued BCD phenotypes, whereas glucosylceramide reduction did not affect the BCD phenotype. Our data provide evidence that reducing intracellular free cholesterol may have therapeutic efficacy in patients with BCD.
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