Modeling disrupted synapse formation in wolfram syndrome using hESCs-derived neural cells and cerebral organoids identifies Riluzole as a therapeutic molecule.
Modeling disrupted synapse formation in wolfram syndrome using hESCs-derived neural cells and cerebral organoids identifies Riluzole as a therapeutic molecule.
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DOI：
10.1038/s41380-023-01987-3
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发表时间：
2023-04
影响因子：
11
通讯作者：
Li, Weida
中科院分区：
文献类型：
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作者：
Yuan, Fei;Li, Yana;Hu, Rui;Gong, Mengting;Chai, Mengyao;Ma, Xuefei;Cha, Jiaxue;Guo, Pan;Yang, Kaijiang;Li, Mushan;Xu, Minglu;Ma, Qing;Su, Qiang;Zhang, Chuan;Sheng, Zhejin;Wu, Heng;Wang, Yuan;Yuan, Wen;Bian, Shan;Shao, Li;Zhang, Ru;Li, Kaicheng;Shao, Zhen;Zhang, Zhen-Ning;Li, Weida
神经突起生长和突触形成失调是许多精神疾病的基础，也表现为钨综合征（WS）。致病基因WFS 1缺陷是否以及如何影响突触形成仍然是一个谜。通过用脑类器官反映人脑发育，WFS 1缺陷的脑类器官不仅重现了WS患者的神经元损失，而且还表现出与星形胶质细胞减少相关的突触形成和功能显著受损。神经元中的WFS 1缺乏自主地延迟神经元分化，改变与精神疾病相关的基因的表达，并且损害神经突生长和突触形成，升高胞质钙。有趣的是，星形胶质细胞中的WFS 1缺陷通过NF-κB活化降低谷氨酸转运体EAAT 2的表达，并诱导过量的谷氨酸。当与野生型神经元共培养时，WFS 1缺陷型星形胶质细胞导致神经元中神经突生长受损和胞质钙增加。重要的是，通过恢复星形胶质细胞中的EAAT 2表达，阿曲唑治疗有效逆转了WFS 1缺陷型脑类器官中受损的突触形成和功能以及受WFS 1缺陷型星形胶质细胞影响的受损的神经突生长。此外，阿舒唑挽救了Wfs 1条件性基因敲除小鼠强迫游泳试验中的抑郁样行为以及新物体试验和水迷宫试验中受损的识别和空间记忆。总而言之，我们的研究为WFS 1缺陷如何影响突触形成和功能提供了新的见解，并提供了治疗这种疾病的策略。
Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders, which are also manifested by wolfram syndrome (WS). Whether and how the causative gene WFS1 deficiency affects synapse formation remain elusive. By mirroring human brain development with cerebral organoids, WFS1-deficient cerebral organoids not only recapitulate the neuronal loss in WS patients, but also exhibit significantly impaired synapse formation and function associated with reduced astrocytes. WFS1 deficiency in neurons autonomously delays neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impairs neurite outgrowth and synapse formation with elevated cytosolic calcium. Intriguingly, WFS1 deficiency in astrocytes decreases the expression of glutamate transporter EAAT2 by NF-κB activation and induces excessive glutamate. When co-cultured with wildtype neurons, WFS1-deficient astrocytes lead to impaired neurite outgrowth and increased cytosolic calcium in neurons. Importantly, disrupted synapse formation and function in WFS1-deficient cerebral organoids and impaired neurite outgrowth affected by WFS1-deficient astrocytes are efficiently reversed with Riluzole treatment, by restoring EAAT2 expression in astrocytes. Furthermore, Riluzole rescues the depressive-like behavior in the forced swimming test and the impaired recognition and spatial memory in the novel object test and water maze test in Wfs1 conditional knockout mice. Altogether, our study provides novel insights into how WFS1 deficiency affects synapse formation and function, and offers a strategy to treat this disease.
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影响因子：
5.1
作者：
GUNN, T;BORTOLUSSI, R;BELMONTE, MM
通讯作者：
BELMONTE, MM
影响因子：
34.7
作者：
Clarke, Laura E.;Barres, Ben A.
通讯作者：
Barres, Ben A.
影响因子：
4.2
作者：
Carbone M;Duty S;Rattray M
通讯作者：
Rattray M
影响因子：
25
作者：
Ballas, Nurit;Lioy, Daniel T.;Grunseich, Christopher;Mandel, Gail
通讯作者：
Mandel, Gail
影响因子：
64.8
作者：
通讯作者：
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