Transcriptome analyses of the cortex and white matter of focal cortical dysplasia type II human samples: novel insights into disease mechanisms and contributions to tissue characterization

Focal cortical dysplasia (FCD) is a common cause of pharmacoresistant epilepsy. According to the 2011 International League Against Epilepsy classification, FCD type II is characterized by dysmorphic neurons (IIa and IIb) and may be associated with balloon cells (IIb). We present a multicentric study to evaluate the transcriptomes of the gay and white matters of surgical FCD type II specimens. Our aim was to contribute to pathophysiology and tissue characterization. We investigated FCD II (a and b) and control samples by performing RNA-sequencing followed by immunohistochemical validation by means of digital analyses. We found 342 and 399 transcripts differentially expressed in the gray matter of IIa and IIb lesions compared to controls, respectively. The top enriched cellular pathway in IIa and IIb gray matter was cholesterol biosynthesis, their genes HMGCS1, HMGCR and SQLE being upregulated in both type II groups. We also found 12 differentially expressed genes when comparing transcriptomes of IIa and IIb lesions. Only 1 transcript (MTRNR2L12) was significantly upregulated in FCD IIa. The white matter in IIa and IIb lesions showed 2 and 24 transcripts differentially expressed respectively compared to controls. No enriched cellular pathways were detected. GPNMB, not previously described in FCD samples, was upregulated in IIb compared to IIa and control groups. Upregulations of cholesterol biosynthesis enzymes and GPNMB genes in FCD groups were immunohistochemically validated. Such enzymes were mainly detected in both dysmorphic and normal neurons, whereas GPNMB was observed only in balloon cells. Overall, our study contributed to the identification of cortical enrichment of cholesterol biosynthesis in FCD type II, which may correspond to neuroprotective response to seizures. Moreover, specific analyses in either the gay or the white matter revealed upregulations of MTRNR2L12 and GPNMB, which might be potential neuropathological biomarkers of a cortex chronically exposed to seizures and of balloon cells, respectively. Overall design: Comparative study of gray and white matter of human frontal lobe tissue surgically obtained from FCD II (a and b) patients and control samples (obtained from adults submitted to autopsy -between 6 and 12 hours post mortem) by performing RNA-sequencing