Jiao Li¹ • Yiqiong Liu¹ • Qin Li¹ • Xiaolin Huang¹ • Dingxi Zhou¹ • Hanjian Xu¹ • Feng Zhao¹ • Xiaoxiao Mi¹ • Ruoxu Wang³ • Fan Jia² • Fuqiang Xu² • Jing Yang¹ • Dong Liu¹ • Xuliang Deng¹ • Yan Zhang¹

¹ 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

² Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China

³ College of Life Sciences, Wuhan University, Wuhan 430027, China

Abstract

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.

Keywords

SGCE; MDS; Filopodia; Synapse; Excitability

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