mTOR cascade activation distinguishes tubers from focal cortical dysplasia
ABSTRACT Balloon cells (BCs) in focal cortical dysplasia (FCD) and giant cells (GCs) in tubers of the tuberous sclerosis complex (TSC) share phenotypic similarities. TSC1 or TSC2 gene mutations in TSC lead to mTOR pathway activation and p70S6kinase (phospho-S6K) and ribosomal S6 (phospho-S6) protein phosphorylation. Phospho-S6K, phospho-S6, and phospho-S6K-activated proteins phospho-STAT3 and phospho-4EBP1 were detected immunohistochemically in GCs, whereas only phospho-S6 was observed in BCs. Expression of four candidate gene families (cell signaling, cell adhesion, growth factor/receptor, and transcription factor mRNAs) was assayed in single, microdissected phospho-S6-immunolabeled BCs and GCs as a strategy to define whether BCs and GCs exhibit differential transcriptional profiles. Among 60 genes, differential expression of 24 mRNAs distinguished BCs from GCs and only 4 genes showed similar expression profiles between BCs and GCs. Tuberin mRNA levels were reduced in GCs from TSC patients with TSC2 gene mutations but were unchanged in BCs. Phospho-S6K, -S6, -STAT3, and -4EBP1 expression in GCs reflects loss of hamartin-tuberin-mediated mTOR pathway inhibition. Phospho-S6 expression alone in BCs does not support mTOR cascade activation in FCD. Differential gene expression profiles in BCs and GCs supports the hypothesis that these cell types derive by distinct pathogenic mechanisms.
- SourceAvailable from: Sergey Shityakov[Show abstract] [Hide abstract]
ABSTRACT: Tuberous sclerosis complex (TSC), caused by dominant mutations in either TSC1 or TSC2 tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless heterozygote Tsc1+/− mice show functional upregulation of cortical GluN2C-containing N-methyl-D-aspartate receptors (NMDARs) in an mTOR-dependent manner and exhibit recurrent, unprovoked seizures during early postnatal life (<P19). Seizures are generated intracortically in the granular layer of the neocortex. Slow kinetics of aberrant GluN2C-mediated currents in spiny stellate cells promotes excessive temporal integration of persistent NMDAR-mediated recurrent excitation and seizure generation. Accordingly, specific GluN2C/D antagonists block seizures in Tsc1+/− mice in vivo and in vitro. Likewise, GluN2C expression is upregulated in TSC human surgical resections, and a GluN2C/D antagonist reduces paroxysmal hyperexcitability. Thus, GluN2C receptor constitutes a promising molecular target to treat epilepsy in TSC patients.Nature Communications 08/2014; DOI:10.1038/ncomms5563 · 10.74 Impact Factor
Article: The Neurology of mTOR[Show abstract] [Hide abstract]
ABSTRACT: The mechanistic target of rapamycin (mTOR) signaling pathway is a crucial cellular signaling hub that, like the nervous system itself, integrates internal and external cues to elicit critical outputs including growth control, protein synthesis, gene expression, and metabolic balance. The importance of mTOR signaling to brain function is underscored by the myriad disorders in which mTOR pathway dysfunction is implicated, such as autism, epilepsy, and neurodegenerative disorders. Pharmacological manipulation of mTOR signaling holds therapeutic promise and has entered clinical trials for several disorders. Here, we review the functions of mTOR signaling in the normal and pathological brain, highlighting ongoing efforts to translate our understanding of cellular physiology into direct medical benefit for neurological disorders.Neuron 10/2014; 84(2):275-291. DOI:10.1016/j.neuron.2014.09.034 · 15.77 Impact Factor
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ABSTRACT: AimPatients with tuberous sclerosis complex (TSC) with brain involvement usually have both tubers and subependymal nodules (SENs) and the occurrence of one lesion without the other seems to be rare. The aim of this study was to assess the specific clinical manifestations and genotype of patients with one type of lesion or the other but not both. Method The magnetic resonance images of 220 patients with TSC were reviewed, and patients with either tubers or SENs, but not both, were identified. ResultsOut of a total of 220 patients (95 males, 125 females; mean age 22y 9mo, range 9mo-81y), six (3%) had tubers without SENs (two males; four females; mean age 34y 10mo, range 11-48y); however, no patients with SENs and without tubers were identified. No mutation was identified (NMI) in any of the six patients who underwent mutational analysis of TSC1 and TSC2. Five of the six patients had three or fewer tubers. InterpretationWe found no patients with SENs but without tubers among our cohort. In all patients with tubers but without SENs, mutational studies of TSC1/TSC2 were negative, and the majority of these had three or fewer tubers. A possible mechanism for patients with NMI and an absence of SENs is a mosaicism with a first postzygotic mutation in the neuroectoderm.Developmental Medicine & Child Neurology 06/2014; 56(12). DOI:10.1111/dmcn.12523 · 2.68 Impact Factor