Lewy Body–like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α‐Synuclein Mutations
Junghyun Jo, Lin Yang, Hoang‐Dai Tran, Weonjin Yu, Alfred Xuyang Sun, Ya Yin Chang, Byung Chul Jung, Seung‐Jae Lee, Tzuen Yih Saw, Bin Xiao, A Khoo, Lai Ping Yaw, Jessica Jiaxin Xie, Hidayat Lokman, Wei‐Yi Ong, Grace Gui Yin Lim, Kah‐Leong Lim, Eng‐King Tan, Huck‐Hui Ng, H. Shawn Je
Abstract
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: 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.