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Title: Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and α-synuclein mutations
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
Keywords: Science::Medicine
Issue Date: 2021
Source: 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.
Project: MOE2014-T2-2-071
NMRC/ TCR/013-NNI/2014
Journal: Annals of Neurology
Abstract: 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.
ISSN: 1531-8249
DOI: 10.1002/ana.26166
Schools: Lee Kong Chian School of Medicine (LKCMedicine) 
School of Biological Sciences 
Organisations: National Neuroscience Institute
Duke-NUS Medical School
Genome Institute of Singapore
National University of Singapore,
Rights: © 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.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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