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Lewy Body–like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α‐Synuclein Mutations
Author(s) -
Jo Junghyun,
Yang Lin,
Tran HoangDai,
Yu Weonjin,
Sun Alfred Xuyang,
Chang Ya Yin,
Jung Byung Chul,
Lee SeungJae,
Saw Tzuen Yih,
Xiao Bin,
Khoo Audrey Tze Ting,
Yaw LaiPing,
Xie Jessica Jiaxin,
Lokman Hidayat,
Ong WeiYi,
Lim Grace Gui Yin,
Lim KahLeong,
Tan EngKing,
Ng HuckHui,
Je Hyunsoo Shawn
Publication year - 2021
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.26166
Subject(s) - lewy body , glucocerebrosidase , organoid , midbrain , mutation , biology , pathology , neuroscience , medicine , parkinson's disease , genetics , gene , central nervous system , disease
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