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

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 (W88C^Mut 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 W88C^Mut 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.