Alterations of phosphatidylinositol 3-kinase pathway components in epilepsy-associated glioneuronal lesions.
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 epilepsy-associated 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 epilepsy-associated glioneuronal lesions will need to be determined in the future.
Schick
Volker
V
Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
Majores
Michael
M
Koch
Arend
A
Elger
Christian E
CE
Schramm
Johannes
J
Urbach
Horst
H
Becker
Albert J
AJ
D000818:Animals; D001927:Brain Diseases / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000201:enzymology*; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004828:Epilepsies, Partial / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D018303:Ganglioglioma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007328:Insulin / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014402:Tuberous Sclerosis / Q000201:enzymology / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000099149:Ezrin
D003598:Cytoskeletal Proteins; D007328:Insulin; D008565:Membrane Proteins; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000099149:Ezrin; C000624650:TSC1 protein, human; C071058:moesin; C071776:radixin