Increased activation of the WNT pathway in brain tissue from patients with cortical dysplasia type IIb.

Focal cortical dysplasia (FCD) is a malformation of cortical development characterized by a heterogeneous group of lesions with high epileptogenic activity. Somatic mutations in the mTOR pathway are the primary cause of cortical malformations (MCDs). Activation of the WNT pathway inhibits GSK3, which is a key inhibitor of mTOR; consequently, WNT activation is associated with increased activation of the mTOR pathway. Residual samples were obtained from the neocortex of five patients diagnosed with FCD type IIb who underwent surgery. For the control group, residual samples from the neocortex of 3 patients with temporal lobe epilepsy associated with hippocampal sclerosis (TLE-HS) were used. The samples were used to evaluate relative gene expression levels, immunohistochemical characteristics, and the quantification of proteins related to the WNT pathway by Western blot. Gene expression analysis showed increased fold-changes in the genes LRP5, LRP6, DKK1, and DVL1. Immunohistochemistry analysis revealed that the FCD brain samples exhibited more staining for LRP6 compared to control brain tissue. All patients with FCD showed stronger staining for β-catenin. The increased gene expression of WNT pathway genes, combined with the intensified anti-LRP6 antibody staining and increased β-catenin staining, along with the reduced rate of β-catenin phosphorylation observed in patients with FCD, suggests a more pronounced activation of the WNT pathway.