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dc.contributor.authorJo, Junghyunen_US
dc.contributor.authorYang, Linen_US
dc.contributor.authorTran, Hoang-Daien_US
dc.contributor.authorYu, Weonjinen_US
dc.contributor.authorSun, Alfred Xuyangen_US
dc.contributor.authorChang, Ya Yinen_US
dc.contributor.authorJung, Byung Chulen_US
dc.contributor.authorLee, Seung-Jaeen_US
dc.contributor.authorSaw, Tzuen Yihen_US
dc.contributor.authorXiao, Binen_US
dc.contributor.authorKhoo, Audrey Tze Tingen_US
dc.contributor.authorYaw, Lai-Pingen_US
dc.contributor.authorXie, Jessica Jiaxinen_US
dc.contributor.authorLokman, Hidayaten_US
dc.contributor.authorOng, Wei-Yien_US
dc.contributor.authorLim, Grace Gui Yinen_US
dc.contributor.authorLim, Kah-Leongen_US
dc.contributor.authorTan, Eng-Kingen_US
dc.contributor.authorNg, Huck-Huien_US
dc.contributor.authorJe, Hyunsoo Shawnen_US
dc.identifier.citationJo, 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.
dc.description.abstractObjective: 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.en_US
dc.description.sponsorshipAgency for Science, Technology and Research (A*STAR)en_US
dc.description.sponsorshipMinistry of Education (MOE)en_US
dc.description.sponsorshipNational Medical Research Council (NMRC)en_US
dc.description.sponsorshipNational Research Foundation (NRF)en_US
dc.relationNMRC/ TCR/013-NNI/2014en_US
dc.relation.ispartofAnnals of Neurologyen_US
dc.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.en_US
dc.titleLewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and α-synuclein mutationsen_US
dc.typeJournal Articleen
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en_US
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.contributor.organizationNational Neuroscience Instituteen_US
dc.contributor.organizationDuke-NUS Medical Schoolen_US
dc.contributor.organizationGenome Institute of Singaporeen_US
dc.contributor.organizationNational University of Singapore,en_US
dc.description.versionPublished versionen_US
dc.subject.keywordsEmbryonic Stem Cellsen_US
dc.description.acknowledgementThis 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).en_US
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