Lewy Body-like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α-Synuclein Mutations

Autor: Hidayat Lokman, Huck-Hui Ng, Audrey Tze Ting Khoo, Wei-Yi Ong, Junghyun Jo, Grace Lim, Hoang Dai Tran, Seung-Jae Lee, Weonjin Yu, Lin Yang, Lai Ping Yaw, Ya Yin Chang, Jessica Jiaxin Xie, Kah-Leong Lim, Bin Xiao, Eng-King Tan, Tzuen Yih Saw, Byung Chul Jung, Alfred Xuyang Sun, Hyunsoo Shawn Je
Přispěvatelé: 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
Rok vydání: 2021
Předmět:
Zdroj: Annals of neurology. 90(3)
ISSN: 1531-8249
Popis: 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).
Databáze: OpenAIRE
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