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Reduction of lipid accumulation rescues Bietti’s crystalline dystrophy phenotypes

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...

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Autores principales: Hata, Masayuki, Ikeda, Hanako O., Iwai, Sachiko, Iida, Yuto, Gotoh, Norimoto, Asaka, Isao, Ikeda, Kazutaka, Isobe, Yosuke, Hori, Aya, Nakagawa, Saori, Yamato, Susumu, Arita, Makoto, Yoshimura, Nagahisa, Tsujikawa, Akitaka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899444/
https://www.ncbi.nlm.nih.gov/pubmed/29581279
http://dx.doi.org/10.1073/pnas.1717338115
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author Hata, Masayuki
Ikeda, Hanako O.
Iwai, Sachiko
Iida, Yuto
Gotoh, Norimoto
Asaka, Isao
Ikeda, Kazutaka
Isobe, Yosuke
Hori, Aya
Nakagawa, Saori
Yamato, Susumu
Arita, Makoto
Yoshimura, Nagahisa
Tsujikawa, Akitaka
author_facet Hata, Masayuki
Ikeda, Hanako O.
Iwai, Sachiko
Iida, Yuto
Gotoh, Norimoto
Asaka, Isao
Ikeda, Kazutaka
Isobe, Yosuke
Hori, Aya
Nakagawa, Saori
Yamato, Susumu
Arita, Makoto
Yoshimura, Nagahisa
Tsujikawa, Akitaka
author_sort Hata, Masayuki
collection PubMed
description 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.
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spelling pubmed-58994442018-04-17 Reduction of lipid accumulation rescues Bietti’s crystalline dystrophy phenotypes Hata, Masayuki Ikeda, Hanako O. Iwai, Sachiko Iida, Yuto Gotoh, Norimoto Asaka, Isao Ikeda, Kazutaka Isobe, Yosuke Hori, Aya Nakagawa, Saori Yamato, Susumu Arita, Makoto Yoshimura, Nagahisa Tsujikawa, Akitaka Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2018-04-10 2018-03-26 /pmc/articles/PMC5899444/ /pubmed/29581279 http://dx.doi.org/10.1073/pnas.1717338115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Hata, Masayuki
Ikeda, Hanako O.
Iwai, Sachiko
Iida, Yuto
Gotoh, Norimoto
Asaka, Isao
Ikeda, Kazutaka
Isobe, Yosuke
Hori, Aya
Nakagawa, Saori
Yamato, Susumu
Arita, Makoto
Yoshimura, Nagahisa
Tsujikawa, Akitaka
Reduction of lipid accumulation rescues Bietti’s crystalline dystrophy phenotypes
title Reduction of lipid accumulation rescues Bietti’s crystalline dystrophy phenotypes
title_full Reduction of lipid accumulation rescues Bietti’s crystalline dystrophy phenotypes
title_fullStr Reduction of lipid accumulation rescues Bietti’s crystalline dystrophy phenotypes
title_full_unstemmed Reduction of lipid accumulation rescues Bietti’s crystalline dystrophy phenotypes
title_short Reduction of lipid accumulation rescues Bietti’s crystalline dystrophy phenotypes
title_sort reduction of lipid accumulation rescues bietti’s crystalline dystrophy phenotypes
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899444/
https://www.ncbi.nlm.nih.gov/pubmed/29581279
http://dx.doi.org/10.1073/pnas.1717338115
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