mTOR and MAPK: from localized translation control to epilepsy

Abstract

BackgroundEpilepsy is one of the most common neurological diseases characterized by excessive hyperexcitability of neurons. Molecular mechanisms of epilepsy are diverse and not really understood. All in common is the misregulation of proteins that determine excitability such as potassium and sodium channels as well as GABA receptors; which are all known as biomarkers for epilepsy. Two recently identified key pathways involve the kinases mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinases (MAPK). Interestingly, mRNAs coding for those biomarkers are found to be localized at or near synapses indicating a local misregulation of synthesis and activity.ResultsResearch in the last decade indicates that RNA-binding proteins (RBPs) responsible for mRNA localization, stability and translation mediate local expression control. Among others, they are affected by mTOR and MAPK to guide expression of epileptic factors. These results suggest that mTOR/MAPK act on RBPs to regulate the fate of mRNAs, indicating a misregulation of protein expression at synapses in epilepsy.ConclusionWe propose that mTOR and MAPK regulate RBPs, thereby guiding the local expression of their target-mRNAs encoding for markers of epilepsy. Thus, misregulated mTOR/MAPK-RBP interplay may result in excessive local synthesis of ion channels and receptors thereby leading to hyperexcitability. Continuous stimulation of synapses further activates mTOR/MAPK pathway reinforcing their effect on RBP-mediated expression control establishing the basis for epilepsy. Here, we highlight findings showing the tight interplay between mTOR as well as MAPK with RBPs to control expression for epileptic biomarkers.

Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses

“…An IPA network formed using these 36 genes as input, but allowed to expand to 70 genes on network formation to identify interaction partners (figure 2) contained three hubs not found within the CNVs themselves. Two hubs, AKT1/2/3 part of the mTOR pathway (mutated in focal cortical dysplasia38) and ERK1/2 (also known as MAP kinases 1 and 2), are important regulators of synaptic excitability involved in epilepsy in animal models and human disease 39. Six other genes within the network, not found in these RE CNVs, are also epilepsy candidates, indicating the strength of this approach for finding disrupted gene pathways (figure 2).…”

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

“…Protein synthesis may shift towards greater production of both pro-epileptic factors and compensatory anti-epileptic factors [71]. Also, dysregulated mTOR signaling, part of the proteomic signature of epilepsy, may stimulate excessive synthesis of ion channels and receptors, leading to hyperexcitability [72].…”

Transcriptome analysis suggests a role for the differential expression of cerebral aquaporins and the MAPK signalling pathway in human temporal lobe epilepsy

“…The MAPK family consists of three major pathways, the extracellular signalregulated kinase (ERK) pathway, the p38 pathway and C-Jun Nterminal kinases (JNK) pathway. The MAPK pathway has been implicated in increased epileptic seizures due to hippocampal sclerosis (Pernice et al, 2016). The purpose of this current study was to analyse gene expression and protein profiling in TLE-HS and the non-sclerotic temporal lobe that had no ictal or inter-ictal activity (TLE-NC; neocortex).…”