FCD Type II and mTOR pathway: Evidence for different mechanisms involved in the pathogenesis of dysmorphic neurons

Rossini, Laura; Villani, Flavio; Granata, Tiziana; Tassi, Laura; Tringali, Giovanni; Cardinale, Francesco; Aronica, Eleonora; Spreafico, Roberto; Garbelli, Rita

doi:10.1016/j.eplepsyres.2016.12.002

Cited by 26 publications

(32 citation statements)

References 45 publications

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“…In this study, FCD samples were used as a positive control group, and indeed our study confirms previous reports showing strong induction of both mTORC1 and mTORC2 in these cases. [33][34][35][36][37][38][39][40]90 However, our FCD cohort data also revealed several distinct features with respect to upstream and downstream mechanisms. Upstream PI3K signaling did not appear to be activated, but rather suppressed in our FCD cohort, as suggested by lower p-Akt (Thr 308) expression, which apparently contradicts previous studies.…”

Section: Discussionmentioning

confidence: 65%

“…Upstream PI3K signaling did not appear to be activated, but rather suppressed in our FCD cohort, as suggested by lower p-Akt (Thr 308) expression, which apparently contradicts previous studies. 33,[37][38][39][40] However, the small number of samples analyzed here may be responsible for these differences. We also found that mTORC2 induction in FCD was accompanied by strong GSK-3b inhibition, but it seemed insufficient to cause a robust suppression of FoxO3a signaling.…”

Section: Discussionmentioning

confidence: 84%

“…A possible explanation for this discrepancy is that in FCD type II specimens, p-Akt (Ser473) is mainly expressed in the neuronal cytoplasm and not in the nucleus. 33,35,38,39 Conclusion Epileptogenesis involves activation of numerous signaling pathways that ultimately result in synaptic reorganization. The mTORC1 and mTORC2 pathways are clearly engaged in human TLE epileptogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…2F-J). [33][34][35][36][37][38][39][40] Next, we performed correlation analyses in TLE patients to establish potential associations of these markers with clinical variables (Table). Hippocampal tissue analysis demonstrated no association between epilepsy duration and expression levels of p-mTOR (Ser2448), or specific mTORC1 and mTORC2 activation markers.…”

Section: Increased Mtorc1 and Mtorc2 Activation In Human Tlementioning

confidence: 99%

See 3 more Smart Citations

Mechanistic target of rapamycin complex 1 and 2 in human temporal lobe epilepsy

Talos

Jacobs

Gourmaud

et al. 2018

Annals of Neurology

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Increased Mtorc1 and Mtorc2 Activation In Human Tlementioning

confidence: 99%

See 2 more Smart Citations

Mechanistic target of rapamycin complex 1 and 2 in human temporal lobe epilepsy

Talos

Jacobs

Gourmaud

et al. 2018

Annals of Neurology

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“…These findings support the idea that additional factors other than the genetic drivers in malformations of cortical development, like OS and the resulting inflammation, could contribute to the histopathological features in FCD IIb and cortical tubers in TSC. In line with this, a recent study addressing the ontogenetic processes at the origin of the complex cytological alteration in FCD type II suggests the concomitant occurrence of two different events: the first very early during cortical development related to the somatic gene mutation acting on mTOR pathway and the second one, promoted by the presence of inflammatory processes that could be responsible for a second wave of cytoarchitectural abnormalities .…”

Section: Discussionmentioning

confidence: 69%

Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence

et al. 2018

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Oxidative stress (OS) occurs in brains of patients with epilepsy and coincides with brain inflammation, and both phenomena contribute to seizure generation in animal models. We investigated whether expression of OS and brain inflammation markers co‐occurred also in resected brain tissue of patients with epileptogenic cortical malformations: hemimegalencephaly (HME), focal cortical dysplasia (FCD) and cortical tubers in tuberous sclerosis complex (TSC). Moreover, we studied molecular mechanisms linking OS and inflammation in an in vitro model of neuronal function. Untangling interdependency and underlying molecular mechanisms might pose new therapeutic strategies for treating patients with drug‐resistant epilepsy of different etiologies. Immunohistochemistry was performed for specific OS markers xCT and iNOS and brain inflammation markers TLR4, COX‐2 and NF‐κB in cortical tissue derived from patients with HME, FCD IIa, IIb and TSC. Additionally, we studied gene expression of these markers using the human neuronal cell line SH‐SY5Y in which OS was induced using H2O2. OS markers were higher in dysmorphic neurons and balloon/giant cells in cortex of patients with FCD IIb or TSC. Expression of OS markers was positively correlated to expression of brain inflammation markers. In vitro, 100 µM, but not 50 µM, of H2O2 increased expression of TLR4, IL‐1β and COX‐2. We found that NF‐κB signaling was activated only upon stimulation with 100 µM H2O2 leading to upregulation of TLR4 signaling and IL‐1β. The NF‐κB inhibitor TPCA‐1 completely reversed this effect. Our results show that OS positively correlates with neuroinflammation and is particularly evident in brain tissue of patients with FCD IIb and TSC. In vitro, NF‐κB is involved in the switch to an inflammatory state after OS. We propose that the extent of OS can predict the neuroinflammatory state of the brain. Additionally, antioxidant treatments may prevent the switch to inflammation in neurons thus targeting multiple epileptogenic processes at once.

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Multiparameter quantitative analyses of diagnostic cells in brain tissues from tuberous sclerosis complex

Arceneaux,

Brockman,

Khurana

et al. 2024

Cytometry Part B Clinical

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The advent of high‐dimensional imaging offers new opportunities to molecularly characterize diagnostic cells in disorders that have previously relied on histopathological definitions. One example case is found in tuberous sclerosis complex (TSC), a developmental disorder characterized by systemic growth of benign tumors. Within resected brain tissues from patients with TSC, detection of abnormally enlarged balloon cells (BCs) is pathognomonic for this disorder. Though BCs can be identified by an expert neuropathologist, little is known about the specificity and broad applicability of protein markers for these cells, complicating classification of proposed BCs identified in experimental models of this disorder. Here, we report the development of a customized machine learning pipeline (BAlloon IDENtifier; BAIDEN) that was trained to prospectively identify BCs in tissue sections using a histological stain compatible with high‐dimensional cytometry. This approach was coupled to a custom 36‐antibody panel and imaging mass cytometry (IMC) to explore the expression of multiple previously proposed BC marker proteins and develop a descriptor of BC features conserved across multiple tissue samples from patients with TSC. Here, we present a modular workflow encompassing BAIDEN, a custom antibody panel, a control sample microarray, and analysis pipelines—both open‐source and in‐house—and apply this workflow to understand the abundance, structure, and signaling activity of BCs as an example case of how high‐dimensional imaging can be applied within human tissues.

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FCD Type II and mTOR pathway: Evidence for different mechanisms involved in the pathogenesis of dysmorphic neurons

Cited by 26 publications

References 45 publications

Mechanistic target of rapamycin complex 1 and 2 in human temporal lobe epilepsy

Mechanistic target of rapamycin complex 1 and 2 in human temporal lobe epilepsy

Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence

Multiparameter quantitative analyses of diagnostic cells in brain tissues from tuberous sclerosis complex

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