The Important Role of Perituberal Tissue in Epileptic Patients with Tuberous Sclerosis Complex by the Transcriptome Analysis

Abstract

Epilepsy is most common in patients with tuberous sclerosis complex (TSC). However, in addition to the challenging treatment, the pathogenesis of epilepsy is still controversial. To determine the transcriptome characteristics of perituberal tissue (PT) and clarify its role in the pathogenesis of epilepsy, GSE16969 was downloaded from the GEO database for further study by comprehensive bioinformatics analysis. Identification of differentially expressed genes (DEGs), functional enrichment analysis, construction of protein-protein interaction (PPI) network, and selection of Hub genes were performed using R language, Metascape, STRING, and Cytoscape, respectively. Comparing with cortical tuber (CT), 220 DEGs, including 95 upregulated and 125 downregulated genes, were identified in PT and mainly enriched in collagen-containing extracellular matrix and positive regulation of receptor-mediated endocytosis, as well as the pathways of ECM-receptor interaction and neuroactive ligand-receptor interaction. As for normal cortex (NC), 1549 DEGs, including 30 upregulated and 1519 downregulated genes, were identified and mainly enriched in presynapse, dendrite and axon, and also the pathways of dopaminergic synapse and oxytocin signaling pathway. In the PPI network, 4 hub modules were found between PT and CT, and top 5 hub modules were selected between PT and NC. C3, APLNR, ANXA2, CD44, CLU, CP, MCHR2, HTR1E, CTSG, APP, and GNG2 were identified as Hub genes, of which, C3, CD44, ANXA2, HTR1E, and APP were identified as Hub-BottleNeck genes. In conclusion, PT has the unique characteristics different from CT and NC in transcriptome and makes us further understand its importance in the TSC-associated epilepsy.

Inhibition of ANXA2 activity attenuates epileptic susceptibility and GluA1 phosphorylation

“…ANXA2, an important annex in family member, was reported to be highly expressed in patients with tuberous sclerosis with seizures. However, it has not been studied in epilepsy 18,38 . Given that synaptic dysfunction is closely associated with epilepsy and that previous reports indicate that ANXA2 plays a major role in the development of excitatory synaptic activity, we speculate that ANXA2 can participate in epileptogenesis by regulating synaptic transmission.…”

“…However, it has not been studied in epilepsy. 18,38 Given AMPAR surface proteins, including GluA1, are dynamically changing; their distribution is tightly regulated, and AMPAR modification is largely dependent on serine phosphorylation of GluA1. 39 Using an immunoprecipitation assay, we found that ANXA2interacts with GluA1 in epileptic hippocampal tissue.…”

“…ANXA2 is expressed in the cortical and hippocampal tissues, where it is involved in various cellular functions such as calcium signaling, cell growth, vesicle transportation, and cell division 16,17 . Earlier studies have reported that dendrites and axons are enriched in ANXA2, where it participates in the regulation of axon growth and excitatory neuronal activity 18,19 . However, it is unknown whether ANXA2 can modulate the pathophysiological process of seizures by regulating excitatory neural activity.…”

“… 16 , 17 Earlier studies have reported that dendrites and axons are enriched in ANXA2, where it participates in the regulation of axon growth and excitatory neuronal activity. 18 , 19 However, it is unknown whether ANXA2 can modulate the pathophysiological process of seizures by regulating excitatory neural activity.…”

Mapping dynamic molecular changes in hippocampal subregions after traumatic brain injury through spatial proteomics

“…To further confirm our results, GFAP and CD44 were selected for validation in tissue sections using immunofluorescence, which showed a consistent trend with proteomics results. These proteins were chosen because blood GFAP is an FDA authorized marker in individuals with suspected TBI [ 23 ] and both the proteins have distinguished roles in synaptic plasticity and neurogenesis, with reported associations in Parkinson’s and dementia [ 24 – 29 ]. CD44 was found to be upregulated in 7 days post-TBI compared to 1 day post-TBI and Sham in all sub-regions except SM where it showed upregulation in both the TBI time points as compared to Sham.…”