Activation of extracellular regulated kinase and mechanistic target of rapamycin pathway in focal cortical dysplasia

Abstract

Neuropathology of resected brain tissue has revealed an association of focal cortical dysplasia (FCD) with drug resistant epilepsy (DRE). Recent studies have shown that the mechanistic target of rapamycin (mTOR) pathway is hyperactivated in FCD as evidenced by increased phosphorylation of the ribosomal protein S6 (S6) at serine 240/244 (S240/244), a downstream target of mTOR. Moreover, extracellular regulated kinase (ERK) has been shown to phosphorylate S6 at serine 235/236 (S235/236) and tuberous sclerosis complex 2 (TSC2) at serine 664 (S664) leading to hyperactive mTOR signaling. We evaluated ERK phosphorylation of S6 and TSC2 in two types of FCD (FCD I and FCDII) as a candidate mechanism contributing to mTOR pathway dysregulation in this disorder. Tissue samples from patients with tuberous sclerosis (TS) served as a positive control. Immunostaining for phospho-S6 (pS6240/244 and pS6235/236), phospho-ERK (pERK), and phospho-TSC2 (pTSC2) was performed on resected brain tissue with FCD and TS. We found increased pS6240/244 and pS6235/236 staining in FCD I, FCD II, and TS compared to normal appearing tissue, while pERK and pTSC2 staining was increased only in FCD IIb and TS tissue. Our results suggest that both the ERK and mTOR pathways are dysregulated in FCD and TS; however, the signaling alterations are different for FCD I as compared to FCD II and TS.

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

“…Another important finding of our study is the robust activation of ERK signaling in both hippocampus and temporal cortex of patients suffering from therapy-resistant TLE, consistent with previous studies showing upregulated ERK signaling in several neocortical epilepsy syndromes, including TSC and FCD (90–92). ERK is upstream of mTORC1 and both kinases are simultaneously induced at activated synapses to regulate local protein synthesis (20).…”

“…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.…”

“…87,89 Another important finding of our study is the robust activation of ERK signaling in both hippocampus and temporal cortex of patients suffering from therapyresistant TLE, consistent with previous studies showing upregulated ERK signaling in several neocortical epilepsy syndromes, including TSC and FCD. [90][91][92] ERK is upstream of mTORC1 and both kinases are simultaneously induced at activated synapses to regulate local protein synthesis. 20 In addition to activating mTOR, ERK also regulates the activity of cAMP response element binding protein and therefore may be critically involved in seizure-induced dysregulated gene expression.…”

Clinical and immunohistochemical characteristics of type II and type I focal cortical dysplasia

“…S6 protein phosphorylation (ser 235/236 and ser 240/244) was not detected in FCD I cases in this study. However, a recent study has reported the expressions of mTOR cascade activation protein was also found in some FCD I cases [26]. They thought the reasons for this discrepancy may be related to variability in the levels of mTOR cascade activation protein in FCD I as well as differences in the type of antibodies, staining techniques, duration of fixation and type of antigen retrieval methods used [26].…”

“…However, a recent study has reported the expressions of mTOR cascade activation protein was also found in some FCD I cases [26]. They thought the reasons for this discrepancy may be related to variability in the levels of mTOR cascade activation protein in FCD I as well as differences in the type of antibodies, staining techniques, duration of fixation and type of antigen retrieval methods used [26]. In addition to these, possible reasons also included the lesser samples on clinical cases and an unclear designation of FCD I or FCD II cases under the condition of lacking BCs or DNs.…”