Lv Junkai, Liang Shiqi, Qin Pengwei, Liu Xinlu, Ge Xiangyu, Guo Yiqing, Xia Shili, Jing Wei, Lu Youming, Zhang Tongmei, Li Hao
Innovation Center for Brain Medical Sciences of the Ministry of Education, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Pathophysiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Sci Adv. 2025 Mar 28;11(13):eadr4588. doi: 10.1126/sciadv.adr4588.
Tourette's syndrome (TS) is a major neurodevelopmental disorder characterized by childhood-onset motor and vocal tics. A W88C mutation in gene is a notable risk factor for TS, but the underlying molecular mechanisms remain unclear due to the lack of suitable animal models. Here, we generate a mutant mouse line with human W88C mutation (W88C mice), which exhibits behavioral deficits similar to those observed in patients with TS, including repetitive motor behaviors and sensorimotor gating abnormalities. The W88C mutation leads to the degradation of kidney and brain (KIBRA) protein via a proteasomal pathway, evokes dopamine release in the dorsal striatum, and disrupts synaptic function through the dysregulation of Hippo pathway. Neuron-specific overexpression of wild-type rescues synaptic and behavioral phenotypes in W88C mice. Together, this study not only provides a valuable mouse model for studying TS but also offers fresh insights into the molecular and synaptic mechanisms underlying neurodevelopmental abnormalities in TS.
图雷特综合征（TS）是一种主要的神经发育障碍，其特征为儿童期起病的运动和发声抽动。基因中的W88C突变是TS的一个显著风险因素，但由于缺乏合适的动物模型，其潜在的分子机制仍不清楚。在这里，我们生成了具有人类W88C突变的突变小鼠品系（W88C小鼠），其表现出与TS患者相似的行为缺陷，包括重复性运动行为和感觉运动门控异常。W88C突变通过蛋白酶体途径导致肾脑蛋白（KIBRA）降解，引起背侧纹状体中多巴胺释放，并通过失调Hippo通路破坏突触功能。野生型的神经元特异性过表达可挽救W88C小鼠的突触和行为表型。总之，本研究不仅为研究TS提供了一个有价值的小鼠模型，也为TS神经发育异常的分子和突触机制提供了新的见解。
