Document detail
ID
oai:pubmedcentral.nih.gov:9543...
Topic
Research ArticlesAuthor
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 ShawnLangue
enEditor
John Wiley & Sons, Inc.
Category
Wiley-Blackwell Online Open
Year
2021
listing date
12/1/2023
Keywords
generated disease carrying parkinson human hmlos body–like inclusionsAbstract
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
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, 2021, Lewy Body–like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α‐Synuclein Mutations, John Wiley & Sons, Inc.
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