Picker, SR; (2014) Molecular Characterisation of Focal Cortical Dysplasia and Tuberous Sclerosis. Doctoral thesis , UCL (University College London).

Abstract

INTRODUCTION: This project focuses on the biological characterisation of 4 important structural causes of severe childhood epilepsy: Focal Cortical Dysplasia (FCD) Type IIb and IIa, and two brain lesions present in Tuberous Sclerosis: cortical tubers and subependymal giant cell astrocytoma (SEGA) tumours. Within these lesions several abnormal cell populations are present, including: Balloon cells, Dysmorphic neurons and SEGA cells. These may represent an aberrant neural progenitor/ stem cell population. This raises the hypothesis that a pathological stem cell contributes to the pathogenesis of these diseases. The aim of this study is to identify molecular networks responsible and/or implicated within these lesions. METHODS: Differentially expressed genes/exons and microRNAs were identified using the Affymetrix human exon ST1 microarray and NanoString platform respectively. This was performed across the FCD subtypes, cortical tubers, SEGAs and normally formed cortex. WGCNA and IPA network analyses were then applied. Selected proteins based on these results, were validated and investigated by immunohistochemistry of surgical material. RESULTS: Hierarchal clustering of the gene expression between samples was able to reclassify the diseases based on the transcriptome rather than diagnostic subtype. Following a systems biology approach, novel functional networks were identified. A micro-network of: Tenascin C, Palladin, Chitinase-3-like 1, and paired-related-homeobox 1 within the FCD IIb lesion was validated at the protein level, with extracellular-signal-regulated kinase (ERK) as its hub.Additionally, a highly robust subset of alternatively spliced exons specific to the BC harbouring samples were identified. 75.9% of genes identified as differentially expressed between FCD IIa and FCD IIb, were potentially explicable due to the microRNA dysregulation identified. CONCLUSION: This is the first published gene, exon and microRNA high-throughput analysis performed concurrently for FCD IIb, FCD IIa, cortical tubers and SEGA tumours and the first use of network analysis in these diseases, potentially leading to new therapeutic targets.

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