Lewy Body-like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α-Synuclein Mutations.
Lewy Body-like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and α-Synuclein Mutations.
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携带葡萄糖脑苷脂酶和α-突触核蛋白突变的人中脑类器官中的Lewy小体样包涵体。
DOI：
10.1002/ana.26166
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发表时间：
2021-09
影响因子：
11.2
通讯作者：
Je, Hyunsoo Shawn
中科院分区：
文献类型：
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作者：
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
我们利用由携带葡萄糖脑苷脂酶基因（GBA 1）和α-突触核蛋白（α-syn; SNCA）扰动的人多能干细胞生成的人中脑样类器官（hMLO）来研究帕金森病中的基因型与表型关系，特别旨在重现hMLO模型中的α-syn和Lewy体相关病理学和神经退行性变过程。我们从GBA 1 −/−和SNCA过表达的同基因胚胎干细胞中产生并表征了hMLO，并在GBA 1/SNCA双扰动hMLO和conduritol-B-环氧化物处理的SNCA三倍hMLO中产生了Lewy小体样包涵体。我们首次发现，葡萄糖脑苷脂酶的丧失，加上野生型α-syn过表达，导致hMLO中耐洗涤剂、富含β-片层的α-syn聚集体和路易体样包涵体的大量积累。这些路易体样包涵体表现出具有嗜酸性核心的球对称形态，含有α-syn和泛素，并且也可以在帕金森病患者来源的hMLO中形成。我们还证明，葡萄糖脑苷脂酶功能受损会促进来自携带SNCA三重体患者的hMLO中路易体样内含物的形成。总之，数据表明，我们的hMLO携带帕金森病的2个主要风险因素（葡萄糖脑苷脂酶缺乏和野生型α-syn过度产生），为进一步阐明进行性路易体形成的潜在机制提供了一个易于处理的模型。神经网络2021;90：490-505
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. 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. 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. 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
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影响因子：
8.6
作者：
Appel-Cresswell, Silke;Vilarino-Guell, Carles;Farrer, Matthew J.
通讯作者：
Farrer, Matthew J.
影响因子：
168.9
作者：
Kalia, Lorraine V.;Lang, Anthony E.
通讯作者：
Lang, Anthony E.
影响因子：
12.8
作者：
Jung, Byung Chul;Lim, Yoon-Ju;Lee, Seung-Jae
通讯作者：
Lee, Seung-Jae
DOI：
10.1126/science.aam9080
发表时间：
2017-09-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Burbulla LF;Song P;Mazzulli JR;Zampese E;Wong YC;Jeon S;Santos DP;Blanz J;Obermaier CD;Strojny C;Savas JN;Kiskinis E;Zhuang X;Krüger R;Surmeier DJ;Krainc D
通讯作者：
Krainc D
影响因子：
21.3
作者：
Fujiwara, H;Hasegawa, M;Iwatsubo, T
通讯作者：
Iwatsubo, T