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

作者：Delia M. Talos, Leah Jacobs, Sarah Gourmaud, Carlos A. Coto, Hongyu Sun, Kuei‐Cheng Lim, Timothy H. Lucas, Kathryn A. Davis, Maria Martinez‐Lage, Frances E. Jensen · 发表于：Annals of Neurology · 年份：2018 · DOI：10.1002/ana.25149 · 被引用次数：76 · 研究领域：Tuberous Sclerosis Complex Research、PI3K/AKT/mTOR signaling in cancer、Glycogen Storage Diseases and Myoclonus

OBJECTIVE: Temporal lobe epilepsy (TLE) is a chronic epilepsy syndrome defined by seizures and progressive neurological disabilities, including cognitive impairments, anxiety, and depression. Here, human TLE specimens were investigated focusing on the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and complex 2 (mTORC2) activities in the brain, given that both pathways may represent unique targets for treatment. METHODS: Surgically resected hippocampal and temporal lobe samples from therapy-resistant TLE patients were analyzed by western blotting to quantify the expression of established mTORC1 and mTORC2 activity markers and upstream or downstream signaling pathways involving the two complexes. Histological and immunohistochemical techniques were used to assess hippocampal and neocortical structural abnormalities and cell-specific expression of individual biomarkers. Samples from patients with focal cortical dysplasia (FCD) type II served as positive controls. RESULTS: We found significantly increased expression of phospho-mTOR (Ser2448), phospho-S6 (Ser235/236), phospho-S6 (Ser240/244), and phospho-Akt (Ser473) in TLE samples compared to controls, consistent with activation of both mTORC1 and mTORC2. Our work identified the phosphoinositide 3-kinase and Ras/extracellular signal-regulated kinase signaling pathways as potential mTORC1 and mTORC2 upstream activators. In addition, we found that overactive mTORC2 signaling was accompanied by induction of two protein k...