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

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 recapitulati...

Full description

Saved in:

Bibliographic Details
Published in:	Annals of neurology Vol. 90; no. 3; pp. 490 - 505
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	Hoboken, USA John Wiley & Sons, Inc 01-09-2021 Wiley Subscription Services, Inc
Subjects:	Embryo cells Genotypes Glucosylceramidase Inclusions Leukocytes (eosinophilic) Lewy bodies Mesencephalon Morphology Movement disorders Mutation Neurodegeneration Neurodegenerative diseases Organoids Parkinson's disease Perturbation Phenotypes Pluripotency Risk analysis Risk factors Stem cells Synuclein Ubiquitin
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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
Bibliography:	† J.J. and L.Y. contributed equally. # E.‐K.T. was the submitting author. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0364-5134 1531-8249
DOI:	10.1002/ana.26166