3 years ago

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

Carlos A Coto, Hongyu Sun, Kuei-Cheng Lim, Delia M. Talos, Sarah Gourmaud, Maria Martinez-Lage, Timothy H. Lucas, Leah M. Jacobs, Kathryn A. Davis, Frances E. Jensen
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, as 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 PI3K and Ras/ERK signaling pathways as potential mTORC1 and mTORC2 upstream activators. In addition, we found that overactive mTORC2 signaling was accompanied by induction of two Akt-dependent pro-survival pathways, as evidenced by increased inhibitory phosphorylation of FoxO3a (Ser253) and GSK-β (Ser9). Interpretation: Our data demonstrate that mTOR signaling is significantly dysregulated in human TLE, offering new targets for pharmacologic interventions. Specifically, clinically available drugs that suppress mTORC1 without compromising mTOR2 signaling, such as rapamycin and its analogs, may represent a new group of antiepileptogenic agents in TLE patients. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/ana.25149

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