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Lewy Body–like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α‐Synuclein Mutations
https://oist.repo.nii.ac.jp/records/2280
https://oist.repo.nii.ac.jp/records/2280a67557ab-9ab2-42a7-bd4d-8aaa48b21bda
名前 / ファイル | ライセンス | アクション |
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Jo-2021-Lewy-bodylike-inclusions-in-human-m (11.2 MB)
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Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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Item type | 学術雑誌論文 / Journal Article(1) | |||||
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公開日 | 2021-09-14 | |||||
タイトル | ||||||
言語 | en | |||||
タイトル | Lewy Body–like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α‐Synuclein Mutations | |||||
言語 | ||||||
言語 | eng | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
資源タイプ | journal article | |||||
著者(英) |
Jo, Junghyun
× Jo, Junghyun× Yang, Lin× Tran, Hoang‐Dai× Yu, Weonjin× Sun, Alfred Xuyang× Chang, Ya Yin× Jung, Byung Chul× Lee, Seung‐Jae× Saw, Tzuen Yih× Xiao, Bin× Khoo, Audrey Tze Ting× Yaw, Lai‐Ping× Xie, Jessica Jiaxin× Lokman, Hidayat× Ong, Wei‐Yi× Lim, Grace Gui Yin× Lim, Kah‐Leong× Tan, Eng‐King× Ng, Huck‐Hui× Je, Hyunsoo Shawn |
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書誌情報 |
en : Annals of Neurology 巻 90, 号 3, p. 490-505, 発行日 2021-08-10 |
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抄録 | ||||||
内容記述タイプ | Other | |||||
内容記述 | Objective We utilized human midbrain-like organoids (hMLOs) generated from human pluripotent stem cells carrying glucocerebrosidase gene (GBA1) and α-synuclein (α-syn; SNCA) perturbations to investigate genotype-to-phenotype relationships in Parkinson disease, with the particular aim of recapitulating α-syn– and Lewy body–related pathologies and the process of neurodegeneration in the hMLO model. Methods We generated and characterized hMLOs from GBA1−/− and SNCA overexpressing isogenic embryonic stem cells and also generated Lewy body–like inclusions in GBA1/SNCA dual perturbation hMLOs and conduritol-b-epoxide–treated SNCA triplication hMLOs. Results We identified for the first time that the loss of glucocerebrosidase, coupled with wild-type α-syn overexpression, results in a substantial accumulation of detergent-resistant, β-sheet–rich α-syn aggregates and Lewy body–like inclusions in hMLOs. These Lewy body–like inclusions exhibit a spherically symmetric morphology with an eosinophilic core, containing α-syn with ubiquitin, and can also be formed in Parkinson disease patient–derived hMLOs. We also demonstrate that impaired glucocerebrosidase function promotes the formation of Lewy body–like inclusions in hMLOs derived from patients carrying the SNCA triplication. Interpretation Taken together, the data indicate that our hMLOs harboring 2 major risk factors (glucocerebrosidase deficiency and wild-type α-syn overproduction) of Parkinson disease provide a tractable model to further elucidate the underlying mechanisms for progressive Lewy body formation. ANN NEUROL 2021;90:490–505 |
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出版者 | ||||||
出版者 | Wiley Periodicals LLC on behalf of American Neurological Association. | |||||
ISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 0364-5134 | |||||
ISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 1531-8249 | |||||
PubMed番号 | ||||||
関連タイプ | isIdenticalTo | |||||
識別子タイプ | PMID | |||||
関連識別子 | info:pmid/34288055 | |||||
DOI | ||||||
関連タイプ | isIdenticalTo | |||||
識別子タイプ | DOI | |||||
関連識別子 | info:doi/10.1002/ana.26166 | |||||
権利 | ||||||
権利情報 | © 2021 The Author(s). | |||||
関連サイト | ||||||
識別子タイプ | URI | |||||
関連識別子 | https://onlinelibrary.wiley.com/doi/full/10.1002/ana.26166 | |||||
著者版フラグ | ||||||
出版タイプ | VoR | |||||
出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 |