Enhanced expression of fragile X mental retardation protein in malformative lesions of patients with focal cortical dysplasia

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Abstract

Focal cortical dysplasia (FCD) accounts for nearly half of all cases of medically refractory epilepsy in the pediatric and adult patient populations. This disorder stems from localized malformations in cortical brain tissue due to impaired neuronal proliferation, differentiation, and migration patterns. Recent studies in animal models have highlighted the potential role of the Fragile X Mental Retardation Protein (FMRP) expression in FCD. Despite this evidence, there has been no investigation into whether this effect is similarly observed in human patients. The purpose of this study is to investigate FMRP expression within localized malformative lesions of patients with FCD. This study also investigates protein expression within the PI3K/Akt/mTOR and canonical Wnt signaling pathways, which have known involvement in epilepsy and interactions with FMRP. Pathologic tissue from malformative lesions of FCD patients with refractory epilepsy were compared to relatively normal control tissue from patients with intracranial neoplasms. A series of western blotting assays were then performed to assess FMRP, as well as key proteins in the PI3K/Akt/mTOR and canonical Wnt signaling pathways. There was reduced S235/236-phophorylated S6, GSK3-alpha, and GSK3-beta protein expression in FCD patient tissue. These patients also expressed significantly greater total and S499-phosphorylated FMRP. Taken together, these findings confirm our hypothesis that malformative lesions of patients with FCD display changes in FMRP expression, as well as dysregulation of both PI3K/Akt/mTOR and canonical Wnt signaling. These novel clinical findings extend previous work in animal models, further suggesting an unforeseen role of FMRP in the pathophysiology of FCD and refractory epilepsy.

Authors

• Conner Douglas Reynolds, University of North Texas Health Science Center

• Suzanne O Nolan, Baylor University

• Gregory D Smith, Baylor University

• Taylor Jefferson, Baylor University

• Samantha Hodges, Baylor University

• Joaquin N Lugo, Baylor University