Early dysregulation of GSK3β impairs mitochondrial activity in Fragile X Syndrome

The finely tuned regulation of mitochondria activity is essential for proper brain development. Fragile X Syndrome (FXS), the leading cause of inherited intellectual disability, is a neurodevelopmental disorder in which mitochondrial dysfunction has been increasingly implicated. This study investigates the role of Glycogen Synthase Kinase 3β (GSK3β) in FXS. Several studies have reported the dysregulation of GSK3β in FXS, and its role in mitochondrial function is also well established. However, the link between disrupted GSK3β activity and mitochondrial dysfunction in FXS remains unexplored. Utilizing Fmr1 knockout (KO) mice and human cell lines from individuals with FXS, we uncovered a developmental window where dysregulated GSK3β activity disrupts mitochondrial function. Notably, a partial inhibition of GSK3β activity in FXS fibroblasts from young individuals rescues the observed mitochondrial defects, suggesting that targeting GSK3β in the early stages may offer therapeutic benefits for this condition. [Display omitted] •GSK3β activity is dysregulated during development in FXS mice and human FXS models.•GSK3β dysregulation affects mitochondrial function in FXS mice and human FXS models.•Inhibition of GSK3β activity rescues mitochondrial defects in human FXS models.