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  2. WWC1 mutation drives dopamine dysregulation and synaptic imbalance in Tourette's syndrome

WWC1 mutation drives dopamine dysregulation and synaptic imbalance in Tourette's syndrome

  • Sci Adv. 2025 Mar 28;11(13):eadr4588. doi: 10.1126/sciadv.adr4588.
Junkai Lv 1 2 Shiqi Liang 1 2 Pengwei Qin 1 2 Xinlu Liu 1 2 Xiangyu Ge 1 2 Yiqing Guo 1 2 Shili Xia 1 2 Wei Jing 1 2 3 Youming Lu 1 2 4 Tongmei Zhang 1 2 5 Hao Li 1 2
Affiliations

Affiliations

  • 1 Innovation Center for Brain Medical Sciences of the Ministry of Education, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 2 Department of Pathophysiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 3 Department of Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 4 Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 4030030, China.
  • 5 Department of Histology and embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Abstract

Tourette's syndrome (TS) is a major neurodevelopmental disorder characterized by childhood-onset motor and vocal tics. A W88C mutation in WWC1 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 (W88CMut 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 WWC1 rescues synaptic and behavioral phenotypes in W88CMut 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.

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