Search

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Inc.)

Bistratene A is a marine toxin which induces phosphorylation of cellular proteins. Our current evidence indicates that this occurs through activation of protein kinase C-delta. In fibroblasts bistratene A causes rounding up of the cells and a rapid disappearance of vinculin staining and actin stress fibers as detected by fluorescence immunohistochemistry. Phosphorylation of the focal adhesion protein, talin, is increased after bistratene A treatment and this is inhibited by calphostin C, a specific inhibitor of PKC. No changes in the phosphorylation status of vinculin, tubulin, or vimentin were observed in the presence of the toxin. Treatment with bistratene A caused a redistribution of PKC-delta from cytosolic and membrane compartments to the nuclear fraction. There was no effect on the subcellular distribution of any other PKC isoform. These results demonstrate that phosphorylation of talin is implicated in the disruption of actin microfilaments in fibroblasts by bistratene A and that this is most likely mediated by PKC-delta.