Li Jiao, Liu Yiqiong, Li Qin, Huang Xiaolin, Zhou Dingxi, Xu Hanjian, Zhao Feng, Mi Xiaoxiao, Wang Ruoxu, Jia Fan, Xu Fuqiang, Yang Jing, Liu Dong, Deng Xuliang, Zhang Yan
State Key Laboratory of Membrane Biology, College of Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Department of Geriatric Dentistry, Peking University School and Hospital of Stomatology, Peking University, Beijing, 100871, China.
College of Life Sciences, Wuhan University, Wuhan, 430027, China.
Neurosci Bull. 2021 Mar;37(3):311-322. doi: 10.1007/s12264-020-00612-5. Epub 2020 Dec 23.
Myoclonus dystonia syndrome (MDS) is an inherited movement disorder, and most MDS-related mutations have so far been found in the ε-sarcoglycan (SGCE) coding gene. By generating SGCE-knockout (KO) and human 237 C > T mutation knock-in (KI) mice, we showed here that both KO and KI mice exerted typical movement defects similar to those of MDS patients. SGCE promoted filopodia development in vitro and inhibited excitatory synapse formation both in vivo and in vitro. Loss of function of SGCE leading to excessive excitatory synapses that may ultimately contribute to MDS pathology. Indeed, using a zebrafish MDS model, we found that among 1700 screened chemical compounds, Vigabatrin was the most potent in readily reversing MDS symptoms of mouse disease models. Our study strengthens the notion that mutations of SGCE lead to MDS and most likely, SGCE functions to brake synaptogenesis in the CNS.
肌阵挛性肌张力障碍综合征（MDS）是一种遗传性运动障碍，迄今为止，大多数与MDS相关的突变都在ε-肌聚糖（SGCE）编码基因中被发现。通过构建SGCE基因敲除（KO）小鼠和人类237 C>T突变敲入（KI）小鼠，我们在此表明，KO小鼠和KI小鼠均表现出与MDS患者相似的典型运动缺陷。SGCE在体外促进丝状伪足的形成，并在体内和体外抑制兴奋性突触的形成。SGCE功能丧失导致兴奋性突触过多，这可能最终导致MDS病理改变。事实上，使用斑马鱼MDS模型，我们发现在1700种筛选的化合物中，氨己烯酸在迅速逆转小鼠疾病模型的MDS症状方面最为有效。我们的研究强化了这样一种观念，即SGCE突变导致MDS，并且很可能SGCE在中枢神经系统中起到抑制突触形成的作用。
