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Title: Reduction of lipid accumulation rescues Bietti’s crystalline dystrophy phenotypes
Authors: Hata, Masayuki
Ikeda, Hanako O.
Iwai, Sachiko
Iida, Yuto
Gotoh, Norimoto
Asaka, Isao  kyouindb  KAKEN_id
Ikeda, Kazutaka
Isobe, Yosuke
Hori, Aya
Nakagawa, Saori
Yamato, Susumu
Arita, Makoto
Yoshimura, Nagahisa
Tsujikawa, Akitaka  kyouindb  KAKEN_id
Author's alias: 畑, 匡侑
池田, 華子
岩井, 祥子
飯田, 悠人
後藤, 謙元
浅香, 勲
池田, 和貴
磯部, 洋輔
堀, あや
中川, 沙織
大和, 進
有田, 誠
吉村, 長久
辻川, 明孝
Keywords: Bietti’s crystalline dystrophy
CYP4V2 gene
induced pluripotent stem
retinal pigment epithelium
Issue Date: 10-Apr-2018
Publisher: National Academy of Sciences
Journal title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 115
Issue: 15
Start page: 3936
End page: 3941
Abstract: 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 δ-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.
Description: 眼の難病クリスタリン網膜症の発症メカニズムを解明 --治療薬の有力候補発見により創薬研究の進展に期待--. 京都大学プレスリリース. 2018-03-27.
Rights: Copyright © 2018 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
DOI(Published Version): 10.1073/pnas.1717338115
PubMed ID: 29581279
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