title: Cortical Tubers: Windows into Dysregulation of Epilepsy Risk and Synaptic Signaling Genes by MicroRNAs.
abstract: Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in the TSC1 and TSC2 genes. Over 80% of TSC patients are affected by epilepsy, but the molecular events contributing to seizures in TSC are not well understood. Recent reports have demonstrated that the brain is enriched with microRNA activity, and they are critical in neural development and function. However, little is known about the role of microRNAs in TSC. Here, we report the characterization of aberrant microRNA activity in cortical tubers resected from 5 TSC patients surgically treated for medically intractable epilepsy. By comparing epileptogenic tubers with adjacent nontuber tissue, we identified a set of 4 coordinately overexpressed microRNAs (miRs 23a, 34a, 34b*, 532-5p). We used quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomic profiling to investigate the combined effect of the 4 microRNAs on target proteins. The proportion of repressed proteins among the predicted targets was significantly greater than in the overall proteome and was highly enriched for proteins involved in synaptic signal transmission. Among the combinatorial targets were TSC1, coding for the protein hamartin, and several epilepsy risk genes. We found decreased levels of hamartin in epileptogenic tubers and confirmed targeting of the TSC1 3' UTR by miRs-23a and 34a.
authors.affiliation: Carman and Ann Adams Department of Pediatrics.
authors.forename: Alan A
authors.initials: AA
authors.lastname: Dombkowski
authors.affiliation: Carman and Ann Adams Department of Pediatrics.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Batista
authors.affiliation: Carman and Ann Adams Department of Pediatrics.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cukovic
authors.affiliation: Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Carruthers
authors.affiliation: Carman and Ann Adams Department of Pediatrics.
authors.forename: Ramya
authors.initials: R
authors.lastname: Ranganathan
authors.affiliation: Carman and Ann Adams Department of Pediatrics.
authors.forename: Upasana
authors.initials: U
authors.lastname: Shukla
authors.affiliation: Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stemmer
authors.affiliation: Carman and Ann Adams Department of Pediatrics Department of Neurology, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit Medical Center, Detroit, MI, USA.
authors.forename: Harry T
authors.initials: HT
authors.lastname: Chugani
authors.affiliation: Carman and Ann Adams Department of Pediatrics.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Chugani
mesh_terms: D001921:Brain / Q000378:metabolism* / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D000069279:Drug Resistant Epilepsy / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism* / Q000601:surgery; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D046228:Microarray Analysis; D016328:NF-kappa B / Q000378:metabolism; D020543:Proteome; D060888:Real-Time Polymerase Chain Reaction; D012306:Risk; D013569:Synapses / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014402:Tuberous Sclerosis / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D000077004:Tuberous Sclerosis Complex 1 Protein; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D016328:NF-kappa B; D020543:Proteome; C000624650:TSC1 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins
keywords: expression profiling; hamartin; proteomics; synapse; tuberous sclerosis complex