Involvement of IRE1α signaling in the hippocampus in patients with mesial temporal lobe epilepsy

Abstract

Cumulative evidence suggests that programmed cell death (apoptosis) may contribute to the progressive hippocampal sclerosis seen in patients with refractory mesial temporal lobe epilepsy (MTLE). The endoplasmic reticulum (ER) stress-mediated cell apoptotic pathway has recently emerged as a vital intrinsic pathway, but the molecular mechanisms underlying this process in the epileptic brain remain unclear. We investigated inositol-requiring protein 1α (IRE1α)-mediated ER stress pro-and anti-apoptotic signaling pathways in resected hippocampi from 32 patients with intractable MTLE. Immunoreactivity for the ER stress markers glucose-regulated proteins 78 and 94 was significantly higher in MTLE hippocampi than in controls. The levels of IRE1α, tumor necrosis factor receptor associated factor 2 (TRAF2), apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK), which together constitute the IRE1α/TRAF2/ASK1/JNK pro-apoptotic signaling pathway, were significantly upregulated in patients with MTLE. Immunoreactivity for caspase-4, a homologue of caspase-12 that is possibly activated by IRE1α via TRAF2 following ER stress, and caspase-3 which was a downstream effector of caspase-4, were both detected in MTLE tissue samples. In contrast, immunoreactivity for caspase-4 and caspase-3 were low or absent in control samples. Simultaneously, the X-box binding protein 1 (XBP1), a basic leucine zipper (bZIP) family transcription factor downstream of IRE1α which can promote cell survival by upregulation of multiple ER-targeted genes, was also overexpressed and activated in MTLE hippocampi. Our data suggest that chronic epilepsy is associated with ER stress, as well as induction of both IRE1α-mediated pro- and anti-apoptotic signaling pathways.