EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 43, No. 5, 231-274, May 2011 Frontier of Epilepsy Research - mTOR signaling pathway Chang-Hoon Cho1,2 symptomatic epilepsy; PP2A, protein phosphatase 2A; PRAS40, proline-rich AKT substrate of 40 KDa; P-REX1, PIP3-dependent 1Epilepsy Research Laboratory Rac exchanger 1; Protor-1, protein observed with RICTOR-1; PTEN, Department of Pediatrics phosphatase and tensin homolog; Rag, Ras-related GTPase; Children’s Hospital of Philadelphia RAPTOR, regulatory-associated protein of mTOR; REDD1, Philadelphia, Pennsylvania, 19104, USA regulated in development and DNA damage responses 1; Rheb, 2 Ras homolog enriched in brain; RICTOR, rapamycin-insensitive Corresponding author: Tel, 1-215-590-0607; companion of mTOR; RSK, RPS6K1 ribosomal protein S6 kinase; Fax, 1-215-590-4142; E-mail, [email protected] S6K, p70 ribosomal protein S6 kinase; SCOP, suprachiasmatic DOI 10.3858/emm.2011.43.5.032 nucleus circadian oscillatory protein; SE, status epilepticus; SF2/ASF, splicing factor, arginine/serine-rich factor; SGK1, serum- Accepted 21 March 2011 and glucocorticoid-induced kinase 1; SHIP-2, SH2-domain con- Available Online 6 April 2011 taining inositol 5-phosphatase 2; SKAR, S6K1 Aly/REF-like target; Abbreviations: 4E-BP, eukaryotic initiation factor 4 (eIF4) binding SREBP, sterol responsive element binding protein; STAT3, signal proteins; ACEA, arachidonyl-2-chloroethylamide; AD, Alzheimer’s transducers and activators of transcription 3; STRADα, STE20- disease; AED, anti-epileptic drug; AICAR, 5-amino-4-imidazole- related adaptor protein α; TBI, traumatic brain injury; TCTP, carboxamide ribose; AKT, acutely transforming retrovirus AKT8 in translationally controlled tumor protein; TNFR, tumor necrosis factor rodent T cell lymphoma; AMPK, AMP-activated protein kinase; AR, receptor; TRADD, TNFR-associated protein with death domain; androgen receptor; ASD, autism spectrum disorder; ASK, apoptosis TSC, tuberous sclerosis complex; ULK1, unc-51-like kinase 1 signal-regulating kinase; BID, BH3-interacting domain death agonist; BIM, Bcl-2-interacting mediator of cell death; BRG1, brahma-related gene 1; CaMKKβ, calcium/calmodulin-dependent protein kinase Abstract kinase β; Cdc42, cell division cycle 42; Cdk, cyclin-dependent kinase; CLIP-170, CAP-GLY domain containing linker protein 1; Studies of epilepsy have mainly focused on the mem- CR, cannabinoid receptor; DAG, diacylgylcerol; DAPK, death- brane proteins that control neuronal excitability. associated protein kinase; DDIT4, DNA-damage-inducible transcript Recently, attention has been shifting to intracellular 4; DEPTOR, DEP-domain containing mTOR-interacting protein; proteins and their interactions, signaling cascades DISC1, disrupted-in-schizophrenia 1; EGF, epidermal growth factor; and feedback regulation as they relate to epilepsy. The eIF4, eukaryotic initiation factor 4; ER, estrogen receptor; FADD, mTOR (mammalian target of rapamycin) signal trans- Fas-associated protein with death domain; FGF, fibroblast growth duction pathway, especially, has been suggested to factor; FKBP12, FK506 binding protein 12; FMRP, fragile X mental play an important role in this regard. These pathways retardation protein; FIP200, focal adhesion kinase interacting protein are involved in major physiological processes as well of 200 KD; FOXO, forkhead box O; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; GSK, glycogen synthase as in numerous pathological conditions. Here, involve- kinase; HCMV, human cytomegalovirus; HSP70, heat shock protein ment of the mTOR pathway in epilepsy will be reviewed 70; HSV, Herpes simplex virus; hVPS34, human vacuolar protein by presenting; an overview of the pathway, a brief de- sorting 34; IGF, insulin-like growth factor; IKKβ, Inhibitor of NF-κB scription of key signaling molecules, a summary of in- kinase β; IP3, inositol triphosphate; IRS-1, insulin receptor dependent reports and possible implications of abnor- substrate-1; LTD, long-term depression; LTP, long-term poten- malities of those molecules in epilepsy, a discussion tiation; mATG13, mammalian autophagy related protein 13; mGluR, of the lack of experimental data, and questions raised metabotrophic glutamate receptor; mLST8, mammalian lethal with for the understanding its epileptogenic mechanism. Sec13 protein 8; Mnk1, MAPK-interacting kinase 1; mSIN-1, mammalian stress-activated protein kinase interacting protein; Keywords: epilepsy; mTOR; rapamycin mTOR, mammalian target of rapamycin, NDRG1, N-myc down- stream regulated gene 1; PA, phosphatidic acid; PAP, phos- phatidate phosphatase; PDCD4, programmed cell death 4; PDK1, Introduction 3-phosphoinositide-dependent protein kinase-1; PGC1α, PPARγ coactivator-1α; PHLPP1/2, PH domain leucine-rich repeat protein In ‘On the sacred disease’, the first book on phosphatase; PI3K, phosphoinositide 3-kinase; PIM-1, provirus epilepsy, Hippocrates correctly described epilepsy integration site for Moloney murine leukemia virus; PIP2, phos- as a brain disorder. However, for hundreds of years, phatidylinositol 4, 5 bisphosphate; PIP3, phosphatidylinositol 3, 4, epilepsy patients have been considered possessed 5 trisphosphate; PMSE, polyhydramnios, megalencephaly and or contagious, and persons with epilepsy have been 232 Exp. Mol. Med. Vol. 43(5), 231-274, 2011 stigmatized, prohibited, or even segregated from their communities. Even today, epilepsy still re- mains a mysterious disease. It is one of the most common neurological problems in the world, and approximately 1% of the general population has epileptic episodes at some point in their lives (WHO, 2005). It has the genetic, environmental, and epigenetic components, and these factors are differentially interwoven in individual patients with various types of epilepsy (Berkovic et al., 2006). Since the first report of an α4 neuronal nicotinic receptor subunit mutation in humans was linked to epilepsy, the list of epileptic mutations in both voltage- and ligand-gated ion channels has conti- nued to grow (Steinlein et al., 1995; Helbig et al., 2008). Thus, the knowledge of molecular mecha- nism of seizures caused by those mutations has been deepened over last decade (Reid et al., 2009). However, genetic defects are only a partial, if not minor, cause of epilepsy. The effectiveness of anti-epileptic drugs (AEDs) against ion channels is limited for the treatment and management of ‘acquired’ epileptic conditions (Beck, 2007). Epileptic seizures result from abnormal synchronous firing of neuronal population (Scharfman, 2007). Since epi- Figure 1. Overview of mTOR signaling pathway. Activation and inhibition lepsy show multiple events; cell death, cell sur- of signaling molecules by phosphorylation are shown in red and blue vival and ectopic neurogenesis, aberrant axonal respectively. sprouting, and synaptic reorganization, the exis- tence of the core signaling pathway involved in these processes should have been expected. How- carpine was injected into rats to induce status ever, we have not been able to have the luxury of epilepticus (SE) and the animals went on to intracellular signaling mechanism for epilepsy like develop spontaneous seizures. It has been shown other neurological diseases until recently (Swiech that S6, a ribosomal protein involved in translation et al., 2008). Here, I will summarize and frame indi- initiation, and a downstream molecule in the mTOR vidual reports of epilepsy-related molecules into signaling pathway, became phosphorylated (acti- the mTOR pathway and try to set the common vated). Treatment of rapamycin, an mTOR kinase ground that can be served for the continuing dis- inhibitor, given either as a pretreatment or given cussion. This may be helpful for researchers espe- after SE, reduced both mossy fiber sprouting, an cially in the epilepsy field who are not familiar with abnormal change in the dentate gyrus and hilus, the intracellular signaling pathway. and seizure frequency (Davenport et al., 1990). Some diseases caused by genetic mutations in the molecules on the mTOR pathway show epi- Known involvement of the mTOR pathway leptic seizures (Figure 2). For example, Tuberous in epilepsy sclerosis complex (TSC), a multi-organ disorder, is mainly caused by mutations in TSC1 and/or TSC2. The mTOR pathway has been studied extensively Its tuber formation is highly associated with mental over the last decade and has been involved both in retardation, autism and epilepsy (Curatolo et al., various normal physiological processes (metabolism, 2008). TSC2, a tumor suppressor forming a com- cell growth, proliferation, differentiation, longevity, plex with TSC1, has been known as a key regulator apoptosis, and autophagy) and several disease of the mTOR kinase, and its functional failure conditions (tumorigenesis, type 2 diabetes, infla- results in uncontrolled mTORC1 activity (Inoki et al, mmation, and neurodegenerative diseases) (Figure 1). 2005). Treatment with rapamycin reduced the sei- Recently, the mTOR pathway has been examined zure frequency in TSC patients and mouse models in animal models of medial temporal lobe epilepsy of TSC (Meikle et al., 2008; Zeng et al., 2008; (Buckmaster et al., 2009; Zeng et al., 2009; Huang Muncy et al., 2009). et al., 2010). In these studies, kainate or pilo- Similarly, PTEN (phosphatase and tensin homo- mTOR pathway in epilepsy 233 having gene deletion in STRADα (Puffenberger et al., 2007) (Figures 2 and 3F). STRADα forms a complex with LKB1 and MO25α, and this complex regulates AMPK which controls mTORC1 and