@article{oai:oist.repo.nii.ac.jp:00002280,
 author = {Jo, Junghyun and Yang, Lin and Tran, Hoang‐Dai and Yu, Weonjin and Sun, Alfred Xuyang and Chang, Ya Yin and Jung, Byung Chul and Lee, Seung‐Jae and Saw, Tzuen Yih and Xiao, Bin and Khoo, Audrey Tze Ting and Yaw, Lai‐Ping and Xie, Jessica Jiaxin and Lokman, Hidayat and Ong, Wei‐Yi and Lim, Grace Gui Yin and Lim, Kah‐Leong and Tan, Eng‐King and Ng, Huck‐Hui and Je, Hyunsoo Shawn},
 issue = {3},
 journal = {Annals of Neurology},
 month = {Aug},
 note = {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},
 pages = {490--505},
 title = {Lewy Body–like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α‐Synuclein Mutations},
 volume = {90},
 year = {2021}
}