Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and α-synuclein mutations

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 recapitulat...

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Main Authors: 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
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
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Language:English
Published: 2022
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Online Access:https://hdl.handle.net/10356/160355
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spelling sg-ntu-dr.10356-1603552023-02-28T17:10:37Z Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and α-synuclein mutations 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 Lee Kong Chian School of Medicine (LKCMedicine) School of Biological Sciences National Neuroscience Institute Duke-NUS Medical School Genome Institute of Singapore National University of Singapore, Science::Medicine Alpha-Synuclein Embryonic Stem Cells 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. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This work was supported by the Singapore Ministry of Education Academic Research Fund (MOE2014-T2-2-071), National Medical Research Council Open-Fund Individual Research Grant (NMRC/OFIRG/0050/2017), National Research Foundation Competitive Research Program (NRFCRP17-2017-04), Duke-NUS Signature Research Program Block Grant (H.S.J.), National Medical Research Council Translational and Clinical Flagship Grant (NMRC/ TCR/013-NNI/2014; E.-K.T., K.-L.L, and H.-H.N.), and Agency for Science, Technology, and Research (H.-H.N). 2022-07-20T00:57:34Z 2022-07-20T00:57:34Z 2021 Journal Article Jo, J., Yang, L., Tran, H., Yu, W., Sun, A. X., Chang, Y. Y., Jung, B. C., Lee, S., Saw, T. Y., Xiao, B., Khoo, A. T. T., Yaw, L., Xie, J. J., Lokman, H., Ong, W., Lim, G. G. Y., Lim, K., Tan, E., Ng, H. & Je, H. S. (2021). Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and α-synuclein mutations. Annals of Neurology, 90(3), 490-505. https://dx.doi.org/10.1002/ana.26166 1531-8249 https://hdl.handle.net/10356/160355 10.1002/ana.26166 34288055 2-s2.0-85112037819 3 90 490 505 en MOE2014-T2-2-071 NMRC/OFIRG/0050/2017 NRFCRP17-2017-04 NMRC/ TCR/013-NNI/2014 Annals of Neurology © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Alpha-Synuclein
Embryonic Stem Cells
spellingShingle Science::Medicine
Alpha-Synuclein
Embryonic Stem Cells
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
Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and α-synuclein mutations
description 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.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
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
format Article
author 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
author_sort Jo, Junghyun
title Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and α-synuclein mutations
title_short Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and α-synuclein mutations
title_full Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and α-synuclein mutations
title_fullStr Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and α-synuclein mutations
title_full_unstemmed Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and α-synuclein mutations
title_sort lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and α-synuclein mutations
publishDate 2022
url https://hdl.handle.net/10356/160355
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