Alterations of Phosphatidylinositol 3‐Kinase Pathway Components in Epilepsy‐associated Glioneuronal Lesions

Abstract

Summary: Low-grade glioneuronal lesions involving tumors such as gangliogliomas and focal cortical dysplasias (FCD) predispose individuals to pharmacoresistant epilepsy. A frequent variant of FCD is composed of dysplastic cytomegalic neurons and Taylor-type balloon cells (FCD IIb ). Those are similar to cellular elements, which are present in cortical tubers in the autosomal dominant inherited tuberous sclerosis complex (TSC). This phacomatosis is caused by mutations in the TSC1 or TSC2 genes. Recent data have indicated accumulation of distinct allelic variants of TSC1 also in FCD IIb . TSC1 represents a key factor in the phosphatidylinositol 3-kinase (PI3K) pathway. A variety of alterations in the PI3K-pathway have been recently reported in epilepsy-associated glioneuronal malformations. Here, we discuss pathogenetic similarities and differences between cortical dysplasias as well epilepsyassociated glioneuronal tumors and TSC-associated cortical tubers with a focus on PI3K-pathway components including ezrin, radixin and moesin (ERM), which represent downstream effectors involved in cytoskeleton-membrane interference. No evidence has been found for mutational events of ERM genes to play a major pathogenetic role in epilepsy-associated glioneuronal malformations. In contrast, aberrant expression of ERM proteins in FCDs and gangliogliomas was observed. These alterations may relate to compromised interactions of dysplastic cellular components in epilepsy-associated glioneuronal lesions and be involved in aberrant PI3K-pathway signaling in epilepsy-associated malformations. However, the underlying cause of PI3K-pathway activation and the functional relationship of PI3K-pathway activity to generation of seizures in epilepsyassociated glioneuronal lesions will need to be determined in the future.

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…2). Although both FCD II and tubers are characterized by mTOR activation slight differences in the phosphorylation signaling steps have been reported [119]. In contrast, activation of the mTOR pathway has not been reported in FCD type I [117,120,121], supporting the notion that FCD I and FCD II represent two pathogenetically distinct entities.…”

Surgery for focal cortical dysplasia in children using intraoperative mapping

“…Considering this, Crino et al [15] hypothesized that focal brain malformations was formed as consequence of somatic gene mutation occurring within a progenitor cell during brain development. Modifications of function of tumor-suppressor genes and the expression of genes that associate with proteins such as radixin, moesin, neurofilament, vimentin, alpha-internexin, and nestin may contribute to disrupted cortical lamination and are observed in dysplastic "balloon" neurons [55,56,62]. These results need confirmation of larger series but seem to be a promising line of evidence to justify the development of MCD.…”

Upregulation of mitogen-activated protein kinase in ganglioglioma

“…Only limited data confirmed the role of proteins belonging to the PI3K/Akt pathway as a possible mechanism of tumorigenesis in GG. However, several studies suggest involvement of the PI3K/Akt signaling cascade in the pathogenesis of glioneuronal lesions, including focal cortical dysplasia [5,19,24]. In a recent report, Boer and colleagues revealed significant activation of PDK1, Akt, mTOR as well as rpS6 and 4E-BP1 in 9 cases of ganglioglioma [5].…”