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http://dx.doi.org/10.3340/jkns.2019.0027

Mechanistic Target of Rapamycin Pathway in Epileptic Disorders  

Kim, Jang Keun (Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST))
Lee, Jeong Ho (Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST))
Publication Information
Journal of Korean Neurosurgical Society / v.62, no.3, 2019 , pp. 272-287 More about this Journal
Abstract
The mechanistic target of rapamycin (mTOR) pathway coordinates the metabolic activity of eukaryotic cells through environmental signals, including nutrients, energy, growth factors, and oxygen. In the nervous system, the mTOR pathway regulates fundamental biological processes associated with neural development and neurodegeneration. Intriguingly, genes that constitute the mTOR pathway have been found to be germline and somatic mutation from patients with various epileptic disorders. Hyperactivation of the mTOR pathway due to said mutations has garnered increasing attention as culprits of these conditions : somatic mutations, in particular, in epileptic foci have recently been identified as a major genetic cause of intractable focal epilepsy, such as focal cortical dysplasia. Meanwhile, epilepsy models with aberrant activation of the mTOR pathway have helped elucidate the role of the mTOR pathway in epileptogenesis, and evidence from epilepsy models of human mutations recapitulating the features of epileptic patients has indicated that mTOR inhibitors may be of use in treating epilepsy associated with mutations in mTOR pathway genes. Here, we review recent advances in the molecular and genetic understanding of mTOR signaling in epileptic disorders. In particular, we focus on the development of and limitations to therapies targeting the mTOR pathway to treat epileptic seizures. We also discuss future perspectives on mTOR inhibition therapies and special diagnostic methods for intractable epilepsies caused by brain somatic mutations.
Keywords
mTORC1; mTORC2; Epilepsy; Malformation of cortical development;
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1 Schwartzkroin PA, Walsh CA : Cortical malformations and epilepsy. Ment Retard Dev Disabil Res Rev 6 : 268-280, 2000   DOI
2 Sim JC, Scerri T, Fanjul-Fernandez M, Riseley JR, Gillies G, Pope K, et al. : Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3. Ann Neurol 79 : 132-137, 2016   DOI
3 Sonenberg N, Hinnebusch AG : Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136 : 731-745, 2009   DOI
4 Southwell AL, Skotte NH, Bennett CF, Hayden MR : Antisense oligonucleotide therapeutics for inherited neurodegenerative diseases. Trends Mol Med 18 : 634-643, 2012   DOI
5 Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A, et al. : Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83 : 1131-1143, 2014   DOI
6 Tavazoie SF, Alvarez VA, Ridenour DA, Kwiatkowski DJ, Sabatini BL : Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci 8 : 1727-1734, 2005   DOI
7 Teutonico A, Schena PF, Di Paolo S : Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus. J Am Soc Nephrol 16 : 3128-3135, 2005   DOI
8 Tokuda S, Mahaffey CL, Monks B, Faulkner CR, Birnbaum MJ, Danzer SC, et al. : A novel Akt3 mutation associated with enhanced kinase activity and seizure susceptibility in mice. Hum Mol Genet 20 : 988-999, 2011   DOI
9 Abu-Remaileh M, Wyant GA, Kim C, Laqtom NN, Abbasi M, Chan SH, et al. : Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science 358 : 807-813, 2017   DOI
10 Alcantara D, Timms AE, Gripp K, Baker L, Park K, Collins S, et al. : Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly. Brain 140 : 2610-2622, 2017   DOI
11 De Benedetti A, Joshi-Barve S, Rinker-Schaeffer C, Rhoads RE : Expression of antisense RNA against initiation factor eIF-4E mRNA in HeLa cells results in lengthened cell division times, diminished translation rates, and reduced levels of both eIF-4E and the p220 component of eIF-4F. Mol Cell Biol 11 : 5435-5445, 1991   DOI
12 Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P : mTOR controls mitochondrial oxidative function through a YY1-PGC-1a transcriptional complex. Nature 450 : 736-740, 2007   DOI
13 Curatolo P, Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T, et al. : Adjunctive everolimus for children and adolescents with treatmentrefractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial. Lancet Child Adolesc Health 2 : 495-504, 2018   DOI
14 D'Gama AM, Geng Y, Couto JA, Martin B, Boyle EA, LaCoursiere CM, et al. : Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol 77 : 720-725, 2015   DOI
15 Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, et al. : TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell 47 : 535-546, 2012   DOI
16 Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M : S6K1- and ${\beta}TRCP$-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314 : 467-471, 2006   DOI
17 Citraro R, Leo A, Constanti A, Russo E, De Sarro G : mTOR pathway inhibition as a new therapeutic strategy in epilepsy and epileptogenesis. Pharmacol Res 107 : 333-343, 2016   DOI
18 Millichap J : Cowden syndrome with cortical malformation and epilepsy. Pediatr Neurol Briefs 34 : 7, 2013
19 Meikle L, Talos DM, Onda H, Pollizzi K, Rotenberg A, Sahin M, et al. : A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J Neurosci 27 : 5546-5558, 2007   DOI
20 Mester J, Eng C : When overgrowth bumps into cancer: the PTEN-opathies. Am J Med Genet C Semin Med Genet 163C : 114-121, 2013   DOI
21 Mirzaa GM, Conway RL, Gripp KW, Lerman-Sagie T, Siegel DH, deVries LS, et al. : Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. Am J Med Genet A 158A : 269-291, 2012   DOI
22 Miyata H, Chiang AC, Vinters HV : Insulin signaling pathways in cortical dysplasia and TSC-tubers: tissue microarray analysis. Ann Neurol 56 : 510-9, 2004   DOI
23 Moosa S, Bohrer-Rabel H, Altmuller J, Beleggia F, Nurnberg P, Li Y, et al. : Smith-Kingsmore syndrome: a third family with the MTOR mutation c.5395G>A p.(Glu1799Lys) and evidence for paternal gonadal mosaicism. Am J Med Genet A 173 : 264-267, 2017   DOI
24 Mroske C, Rasmussen K, Shinde DN, Huether R, Powis Z, Lu HM, et al. : Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities. BMC Med Genet 16 : 102, 2015
25 Muncy J, Butler IJ, Koenig KM : Rapamycin reduces seizure frequency in tuberous sclerosis complex. J Child Neurol 24 : 477, 2009   DOI
26 Avoli M, Bernasconi A, Mattia D, Olivier A, Hwa GG : Epileptiform discharges in the human dysplastic neocortex: in vitro physiology and pharmacology. Ann Neurol 46 : 816-826, 1999   DOI
27 Uhlmann EJ, Wong M, Baldwin RL, Bajenaru ML, Onda H, Kwiatkowski DJ, et al. : Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures. Ann Neurol 52 : 285-296, 2002   DOI
28 Nellist M, Schot R, Hoogeveen-Westerveld M, Neuteboom RF, van der Louw EJ, Lequin MH, et al. : Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia. Mol Genet Metab 114 : 467-473, 2015   DOI
29 Alfaiz AA, Micale L, Mandriani B, Augello B, Pellico MT, Chrast J, et al. : TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease. Hum Mutat 35 : 447-451, 2014   DOI
30 Aronica E, Becker AJ, Spreafico R : Malformations of cortical development. Brain Pathol 22 : 380-401, 2012   DOI
31 Backman SA, Stambolic V, Suzuki A, Haight J, Elia A, Pretorius J, et al. : Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet 29 : 396-403, 2001   DOI
32 Baek ST, Copeland B, Yun EJ, Kwon SK, Guemez-Gamboa A, Schaffer AE, et al. : An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development. Nat Med 21 : 1445-1454, 2015   DOI
33 Banko JL, Poulin F, Hou L, DeMaria CT, Sonenberg N, Klann E : The translation repressor 4E-BP2 is critical for eIF4F complex formation, synaptic plasticity, and memory in the hippocampus. J Neurosci 25 : 9581-9590, 2005   DOI
34 Baple EL, Maroofian R, Chioza BA, Izadi M, Cross HE, Al-Turki S, et al. : Mutations in KPTN cause macrocephaly, neurodevelopmental delay, and seizures. Am J Hum Genet 94 : 87-94, 2014   DOI
35 von der Brelie C, Waltereit R, Zhang L, Beck H, Kirschstein T : Impaired synaptic plasticity in a rat model of tuberous sclerosis. Eur J Neurosci 23 : 686-692, 2006   DOI
36 van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, et al. : Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277 : 805-808, 1997   DOI
37 Venkatesan C, Angle B, Millichap JJ : Early-life epileptic encephalopathy secondary to SZT2 pathogenic recessive variants. Epileptic Disord 18 : 195-200, 2016   DOI
38 Vezina C, Kudelski A, Sehgal SN : Rapamycin (AY-22,989), a new antifungal antibiotic I. Taxonomy of the producing Streptomycete and isolation of the active principle. J Antibiot (Tokyo) 28 : 721-726, 1975   DOI
39 Wahl SE, McLane LE, Bercury KK, Macklin WB, Wood TL : Mammalian target of rapamycin promotes oligodendrocyte differentiation, initiation and extent of CNS myelination. J Neurosci 34 : 4453-4465, 2014   DOI
40 Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM : Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150 : 1196-1208, 2012   DOI
41 Basel-Vanagaite L, Hershkovitz T, Heyman E, Raspall-Chaure M, Kakar N, Smirin-Yosef P, et al. : Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. Am J Hum Genet 93 : 524-529, 2013   DOI
42 European Chromosome 16 Tuberous Sclerosis Consortium : Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75 : 1305-15, 1993   DOI
43 Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, et al. : Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat Med 14 : 843-848, 2008   DOI
44 Eisen T, Sternberg CN, Robert C, Mulders P, Pyle L, Zbinden S, et al. : Targeted therapies for renal cell carcinoma: review of adverse event management strategies. J Natl Cancer Inst 104 : 93-113, 2012   DOI
45 Eng CP, Sehgal SN, Vezina C : Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo) 37 : 1231-1237, 1984   DOI
46 Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al. : Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 337 : 1723-1732, 2017
47 Frankel WN, Yang Y, Mahaffey CL, Beyer BJ, O'Brien TP : Szt2, a novel gene for seizure threshold in mice. Genes Brain Behav 8 : 568-576, 2009   DOI
48 Franz DN, Agricola K, Mays M, Tudor C, Care MM, Holland-Bouley K, et al. : Everolimus for subependymal giant cell astrocytoma: 5-year final analysis. Ann Neurol 78 : 929-938, 2015   DOI
49 Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, et al. : Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol 15 : 1513-1520, 2014   DOI
50 Orloff MS, He X, Peterson C, Chen F, Chen JL, Mester JL, et al. : Germline PIK3CA and AKT1 mutations in cowden and cowden-like syndromes. Am J Hum Genet 92 : 76-80, 2013   DOI
51 Orlova KA, Parker WE, Heuer GG, Tsai V, Yoon J, Baybis M, et al. : STRADa deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice. J Clin Invest 120 : 1591-1602, 2010   DOI
52 Pajusalu S, Reimand T, Ounap K : Novel homozygous mutation in KPTN gene causing a familial intellectual disability-macrocephaly syndrome. Am J Med Genet A 167A : 1913-1915, 2015   DOI
53 Pallet N, Legendre C : Adverse events associated with mTOR inhibitors. Expert Opin Drug Saf 12 : 177-186, 2013   DOI
54 Park SM, Lim JS, Ramakrishina S, Kim SH, Kim WK, Lee J, et al. : Brain somatic mutations in MTOR disrupt neuronal ciliogenesis, leading to focal cortical dyslamination. Neuron 99 : 83-97.e7, 2018   DOI
55 Parker WE, Orlova KA, Parker WH, Birnbaum JF, Krymskaya VP, Goncharov DA, et al. : Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder. Sci Transl Med 5 : 182ra53, 2013   DOI
56 Wolfson RL, Chantranupong L, Wyant GA, Gu X, Orozco JM, Shen K, et al. : KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 543 : 438-442, 2017   DOI
57 Way SW, Mckenna J 3rd, Mietzsch U, Reith RM, Wu HC, Gambello MJ : Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse. Hum Mol Genet 18 : 1252-1265, 2009   DOI
58 Weston MC, Chen H, Swann JW : Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission. J Neurosci 32 : 11441-11452, 2012   DOI
59 Wiemer-Kruel A, Woerle H, Strobl K, Bast T : Everolimus for the treatment of subependymal giant cell astrocytoma probably causing seizure aggravation in a child with tuberous sclerosis complex: a case report. Neuropediatrics 45 : 129-131, 2014   DOI
60 Dutchak PA, Laxman S, Estill SJ, Wang C, Wang Y, Wang Y, et al. : Regulation of hematopoiesis and methionine homeostasis by mTORC1 inhibitor NPRL2. Cell Rep 12 : 371-379, 2015   DOI
61 Jansen LA, Mirzaa GM, Ishak GE, O'Roak BJ, Hiatt JB, Roden WH, et al. : PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain 138(Pt 6) : 1613-1628, 2015   DOI
62 Jung J, Genau HM, Behrends C : Amino acid-dependent mTORC1 regulation by the lysosomal membrane protein SLC38A9. Mol Cell Biol 35 : 2479-2494, 2015   DOI
63 Keppler-Noreuil KM, Parker VE, Darling TN, Martinez-Agosto JA : Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies. Am J Med Genet C Semin Med Genet 172 : 402-421, 2016   DOI
64 Klawitter J, Gottschalk S, Hainz C, Leibfritz D, Christians U, Serkova NJ : Immunosuppressant neurotoxicity in rat brain models: oxidative stress and cellular metabolism. Chem Res Toxicol 23 : 608-619, 2010   DOI
65 Kowalczyk MS, Hughes JR, Babbs C, Sanchez-Pulido L, Szumska D, Sharpe JA, et al. : Nprl3 is required for normal development of the cardiovascular system. Mamm Genome 23 : 404-415, 2012   DOI
66 Krueger DA, Care MM, Agricola K, Tudor C, Mays M, Franz DN : Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology 80 : 574-580, 2013   DOI
67 Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, et al. : Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 369 : 1801-1811, 2010
68 Krueger DA, Wilfong AA, Mays M, Talley CM, Agricola K, Tudor C, et al. : Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology 87 : 2408-2415, 2016   DOI
69 Pilarski R : Cowden syndrome: a critical review of the clinical literature. J Genet Couns 18 : 13-27, 2009   DOI
70 Peters JM, Taquet M, Prohl AK, Scherrer B, van Eeghen AM, Prabhu SP, et al. : Diffusion tensor imaging and related techniques in tuberous sclerosis complex: review and future directions. Future Neurol 8 : 583-597, 2013   DOI
71 Pitkanen A, Lukasiuk K : Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol 10 : 173-186, 2011   DOI
72 Oh WJ, Jacinto E : mTOR complex 2 signaling and functions. Cell Cycle 10 : 2305-2316, 2011   DOI
73 Beaumont V, Zhong N, Fletcher R, Froemke RC, Zucker RS : Phosphorylation and local presynaptic protein synthesis in calcium- and calcineurindependent induction of crayfish long-term facilitation. Neuron 32 : 489-501, 2001   DOI
74 Kuegler PB, Zimmer B, Waldmann T, Baudis B, Ilmjarv S, Hescheler J, et al. : Markers of murine embryonic and neural stem cells, neurons and astrocytes: reference points for developmental neurotoxicity testing. ALTEX 27 : 17-42, 2010
75 Bast T, Ramantani G, Seitz A, Rating D : Focal cortical dysplasia: prevalence, clinical presentation and epilepsy in children and adults. Acta Neurol Scand 113 : 72-81, 2006   DOI
76 Baulac S : MTOR signaling pathway genes in focal epilepsies in Rossignol E, Carmant L, Lacaille JC (eds) : Progress in Brain Research. Amsterdam : Elsevier, 2016, Vol 226, pp61-79
77 Baulac S, Ishida S, Marsan E, Miquel C, Biraben A, Nguyen DK, et al. : Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol 77 : 675-683, 2015   DOI
78 Baybis M, Yu J, Lee A, Golden JA, Weiner H, McKhann G 2nd, et al. : mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann Neurol 56 : 478-487, 2004   DOI
79 Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, et al. : SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 8 : 224-236, 2008   DOI
80 Poduri A, Evrony GD, Cai X, Elhosary PC, Beroukhim R, Lehtinen MK, et al. : Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74 : 41-48, 2012   DOI
81 Raab-Graham KF, Haddick PC, Jan YN, Jan LY : Activity- and mTORdependent suppression of Kv1.1 channel mRNA translation in dendrites. Science 314 : 144-148, 2006   DOI
82 Rabanal-Ruiz Y, Otten EG, Korolchuk VI : mTORC1 as the main gateway to autophagy. Essays Biochem 61 : 565-584, 2017   DOI
83 Blumcke I : Neuropathology of focal epilepsies: a critical review. Epilepsy Behav 15 : 34-39, 2009   DOI
84 Wyant GA, Abu-Remaileh M, Frenkel EM, Laqtom NN, Dharamdasani V, Lewis CA, et al. : Nufip1 is a ribosome receptor for starvation-induced ribophagy. Science 360 : 751-758, 2018   DOI
85 Xiong Q, Oviedo HV, Trotman LC, Zador AM : PTEN regulation of local and long-range connections in mouse auditory cortex. J Neurosci 32 : 1643-1652, 2012   DOI
86 Ben-Sahra I, Howell JJ, Asara JM, Manning BD : Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339 : 1323-1328, 2013   DOI
87 Bercury KK, Dai J, Sachs HH, Ahrendsen JT, Wood TL, Macklin WB : Conditional ablation of raptor or rictor has differential impact on oligodendrocyte differentiation and CNS myelination. J Neurosci 34 : 4466-4480, 2014   DOI
88 Bishop KM : Progress and promise of antisense oligonucleotide therapeutics for central nervous system diseases. Neuropharmacology 120 : 56-62, 2017   DOI
89 Brown EJ, Beal PA, Keith CT, Chen J, Shin TB, Schreiber SL : Control of p70 S6 kinase by kinase activity of FRAP in vivo. Nature 377 : 441-446, 1995   DOI
90 French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, et al. : Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 388 : 2153-2163, 2016   DOI
91 Gingras A, Kennedy SG, O'Leary MA, Sonenberg N, Hay N : 4E-BP1, a repressor of mRNA translation, is phosphorylated by the Akt(PKB) signaling pathway. Genes Dev 12 : 502-513, 1998   DOI
92 Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, et al. : Regulation of 4E-BP1 phosphorylation : a novel two-step mechanism. Genes Dev 13 : 1422-1437, 1999   DOI
93 Gingras AC, Raught B, Sonenberg N : eIF4 initiation factors : effectors of mRNA recruitment of translation. Annu Rev Biochem 68 : 913-963, 1999   DOI
94 Gong X, Zhang L, Huang T, Lin T V., Miyares L, Wen J, et al. : Activating the translational repressor 4E-BP or reducing $S6K-GSK3{\beta}$ activity prevents accelerated axon growth induced by hyperactive mTOR in vivo. Hum Mol Genet 24 : 5746-5758, 2015   DOI
95 Riviere JB, Mirzaa GM, O'Roak BJ, Beddaoui M, Alcantara D, Conway RL, et al. : De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 44 : 934-940, 2012   DOI
96 Rennebeck G, Kleymenova EV, Anderson R, Yeung RS, Artzt K, Walker CL : Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development. Proc Natl Acad Sci U S A 95 : 15629-15634, 1998   DOI
97 Ribierre T, Deleuze C, Bacq A, Baldassari S, Marsan E, Chipaux M, et al. : Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy. J Clin Investig 128 : 2452-2458, 2018   DOI
98 Ricos MG, Hodgson BL, Pippucci T, Saidin A, Ong YS, Heron SE, et al. : Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol 79 : 120-131, 2016   DOI
99 Roy A, Skibo J, Kalume F, Ni J, Rankin S, Lu Y, et al. : Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy. Elife 4 : e12703, 2015   DOI
100 Xu Q, Uliel-Sibony S, Dunham C, Sarnat H, Flores-Sarnat L, Brunga L, et al. : mTOR inhibitors as a new therapeutic strategy in treatment resistant epilepsy in hemimegalencephaly: a case report. J Child Neurol 34 : 132-138, 2019   DOI
101 Yeung RS, Katsetos CD, Klein-szanto A : Subependymal astrocytic hamartomas in the Eker rat model of tuberous sclerosis. Am J Pathol 151 : 1477-1486, 1997
102 Yeung RS, Xiao GH, Jin F, Lee WC, Testa JR, Knudson AG : Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. Proc Natl Acad Sci U S A 91 : 11413-11416, 1994   DOI
103 Yoon BC, Zivraj KH, Holt CE : Local translation and mRNA trafficking in axon pathfinding. Results Probl Cell Differ 48 : 269-288, 2009   DOI
104 Zeng LH, Rensing NR, Zhang B, Gutmann DH, Gambello MJ, Wong M : Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. Hum Mol Genet 20 : 445-454, 2011   DOI
105 Zeng LH, Xu L, Gutmann DH, Wong M : Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 63 : 444-453, 2008   DOI
106 Zoncu R, Efeyan A, Sabatini DM : MTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12 : 21-35, 2011   DOI
107 Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK, et al. : LeucyltRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149 : 410-424, 2012   DOI
108 Gordo G, Tenorio J, Arias P, Santos-Simarro F, Garcia-Minaur S, Moreno JC, et al. : mTOR mutations in Smith-Kingsmore syndrome: four additional patients and a review. Clin Genet 93 : 762-775, 2018   DOI
109 Gu X, Orozco JM, Saxton RA, Condon KJ, Liu GY, Krawczyk PA, et al. : SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358 : 813-818, 2017   DOI
110 Hadamitzky M, Herring A, Kirchhof J, Bendix I, Haight MJ, Keyvani K, et al. : Repeated systemic treatment with rapamycin affects behavior and amygdala protein expression in rats. Int J Neuropsychopharmacol 21 : 592-602, 2018   DOI
111 Kumar V, Zhang MX, Swank MW, Kunz J, Wu G : Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci 25 : 11288-11299, 2005   DOI
112 Kwon CH, Zhu X, Zhang J, Knoop LL, Tharp R, Smeyne RJ, et al. : Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nat Genet 29 : 404-411, 2001   DOI
113 Lee JH, Huynh M, Silhavy JL, Kim S, Dixon-Salazar T, Heiberg A, et al. : De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet 44 : 941-945, 2012   DOI
114 Lee SK, Kim DW : Focal cortical dysplasia and epilepsy surgery. J Epilepsy Res 3 : 43-47, 2013   DOI
115 Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. : mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329 : 959-964, 2010   DOI
116 Lipton JO, Sahin M : The neurology of mTOR. Neuron 84 : 275-291, 2014   DOI
117 Lim JS, Gopalappa R, Kim SH, Ramakrishna S, Lee M, Kim WI, et al. : Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia. Am J Hum Genet 100 : 454-472, 2017   DOI
118 Lim JS, Kim WI, Kang HC, Kim SH, Park AH, Park EK, et al. : Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med 21 : 395-400, 2015   DOI
119 Lin TV, Hsieh L, Kimura T, Malone TJ, Bordey A : Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration. Proc Natl Acad Sci U S A 113 : 11330-11335, 2016   DOI
120 Ljungberg MC, Bhattacharjee MB, Lu Y, Armstrong DL, Yoshor D, Swann JW, et al. : Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia. Ann Neurol 60 : 420-429, 2006   DOI
121 Sarbassov DD, Guertin DA, Ali SM, Sabatini DM : Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307 : 1098-1101, 2005   DOI
122 Sabatini DM : Twenty-five years of mTOR: uncovering the link from nutrients to growth. Proc Natl Acad Sci U S A 114 : 11818-11825, 2017   DOI
123 Capo-Chichi JM, Tcherkezian J, Hamdan FF, Decarie JC, Dobrzeniecka S, Patry L, et al. : Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly. J Med Genet 50 : 740-744, 2013   DOI
124 Cardamone M, Flanagan D, Mowat D, Kennedy SE, Chopra M, Lawson JA : Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex. J Pediatr 164 : 1195-1200, 2014   DOI
125 Carvill GL, Crompton DE, Regan BM, McMahon JM, Saykally J, Zemel M, et al. : Epileptic spasms are a feature of DEPDC5 mTORopathy. Neurol Genet 1 : e17, 2015   DOI
126 Hentges K, Thompson K, Peterson A : The flat-top gene is required for the expansion and regionalization of the telencephalic primordium. Development 126 : 1601-9, 1999   DOI
127 Hiremath LS, Webb NR, Rhoads RE : Immunological detection of the messenger RNA cap-binding protein. J Biol Chem 260 : 7843-7849, 1985   DOI
128 Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH : RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78 : 35-43, 1994   DOI
129 Salinas V, Vega P, Piccirilli MV, Chicco C, Ciraolo C, Christiansen S, et al. : Identification of a somatic mutation in the RHEB gene through high depth and ultra-high depth next generation sequencing in a patient with Hemimegalencephaly and drug resistant Epilepsy. Eur J Med Genet, 2018 [Epub ahead of print]
130 Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, et al. : The rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320 : 1496-1501, 2008   DOI
131 Sare RM, Song A, Loutaev I, Cook A, Maita I, Lemons A, et al. : Negative effects of chronic rapamycin treatment on behavior in a mouse model of fragile X syndrome. Front Mol Neurosci 10 : 452, 2018   DOI
132 Saxton RA, Sabatini DM : mTOR signaling in growth, metabolism, and disease. Cell 168 : 960-976, 2017   DOI
133 Scerri T, Riseley JR, Gillies G, Pope K, Burgess R, Mandelstam SA, et al. : Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5. Ann Clin Transl Neurol 2 : 575-580, 2015   DOI
134 Schick V, Majores M, Engels G, Spitoni S, Koch A, Elger CE, et al. : Activation of Akt independent of PTEN and CTMP tumor-suppressor gene mutations in epilepsy-associated Taylor-type focal cortical dysplasias. Acta Neuropathol 112 : 715-725, 2006   DOI
135 Chen HH, Chen C, Hung SC, Liang SY, Lin SC, Hsu TR, et al. : Cognitive and epilepsy outcomes after epilepsy surgery caused by focal cortical dysplasia in children: early intervention maybe better. Child's Nerv Syst 30 : 1885-1895, 2014   DOI
136 Casadio A, Martin KC, Giustetto M, Zhu H, Chen M, Bartsch D, et al. : A transient, neuron-wide form of creb-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell 99 : 221-237, 1999   DOI
137 Cen Z, Guo Y, Lou Y, Jiang B, Wang J, Feng J : De novo mutation in DEPDC5 associated with unilateral pachygyria and intractable epilepsy. Seizure 50 : 1-3, 2017   DOI
138 Cepeda C, Levinson S, Yazon VW, Barry J, Mathern GW, Fallah A, et al. : Cellular antiseizure mechanisms of everolimus in pediatric tuberous sclerosis complex, cortical dysplasia, and non-mTOR-mediated etiologies. Epilepsia Open 3(Suppl Suppl 2) : 180-190, 2018
139 Cheung KM, Lam CW, Chan YK, Siu WK, Yong L : Atypical focal cortical dysplasia in a patient with Cowden syndrome. Hong Kong Med J 20 : 165-167, 2014
140 Child ND, Cascino GD : Mystery case: Cowden syndrome presenting with partial epilepsy related to focal cortical dysplasia. Neurology 81 : e98-e99, 2013   DOI
141 Huber KM, Kayser MS, Bear MF : Role for rapid dendritic protein synthesis in hippocampal depression. Science 288 : 1254-1257, 2000   DOI
142 Holz MK, Ballif BA, Gygi SP, Blenis J : mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123 : 569-580, 2005   DOI
143 Hou L, Klann E : Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci 24 : 6352-6361, 2004   DOI
144 Hsieh LS, Wen JH, Claycomb K, Huang Y, Harrsch FA, Naegele JR, et al. : Convulsive seizures from experimental focal cortical dysplasia occur in dependently of cell misplacement. Nat Commun 7 : 11753, 2016   DOI
145 Hughes J, Dawson R, Tea M, McAninch D, Piltz S, Jackson D, et al. : Knockout of the epilepsy gene Depdc5 in mice causes severe embryonic dysmorphology with hyperactivity of mTORC1 signalling. Sci Rep 7 : 12618, 2017   DOI
146 Iffland PH 2nd, Crino PB : Focal cortical dysplasia: gene mutations, cell signaling, and therapeutic implications. Annu Rev Pathol 12 : 547-571, 2017   DOI
147 Inoki K, Li Y, Xu T, Guan KL : Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17 : 1829-1834, 2003   DOI
148 Heitman J, Movva NR, Hall MN : Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253 : 905-909, 1991   DOI
149 Ljungberg MC, Sunnen CN, Lugo JN, Anderson AE, D'Arcangelo G : Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of cortical dysplasia. Dis Model Mech 2 : 389-398, 2009   DOI
150 Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J : Rheb binds and regulates the mTOR kinase. Curr Biol 15 : 702-713, 2005   DOI
151 Luikart BW, Schnell E, Washburn EK, Bensen AL, Tovar KR, Westbrook GL : Pten knockdown in vivo increases excitatory drive onto dentate granule cells. J Neurosci 31 : 4345-4354, 2011   DOI
152 Marchese M, Conti V, Valvo G, Moro F, Muratori F, Tancredi R, et al. : Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening. BMC Med Genet 15 : 26, 2014   DOI
153 Marsan E, Baulac S : Review: mechanistic target of rapamycin (mTOR) pathway, focal cortical dysplasia and epilepsy. Neuropathol Appl Neurobiol 44 : 6-17, 2018   DOI
154 Marsan E, Ishida S, Schramm A, Weckhuysen S, Muraca G, Lecas S, et al. : Depdc5 knockout rat: a novel model of mTORopathy. Neurobiol Dis 89 : 180-189, 2016   DOI
155 Martel RR, Klicius J, Galet S : Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can J Physiol Pharmacol 55 : 48-51, 1977   DOI
156 Martinez-Lizana E, Fauser S, Brandt A, Schuler E, Wiegand G, Doostkam S, et al. : Long-term seizure outcome in pediatric patients with focal cortical dysplasia undergoing tailored and standard surgical resections. Seizure 62 : 66-73, 2018   DOI
157 Mc Cormack A, Sharpe C, Gregersen N, Smith W, Hayes I, George AM, et al. : 12q14 microdeletions: additional case series with confirmation of a macrocephaly region. Case Rep Genet 2015 : 192071, 2015
158 Crino PB : The mTOR signalling cascade: paving new roads to cure neurological disease. Nat Rev Neurol 12 : 379-392, 2016   DOI
159 Crino PB : Focal brain malformations: a spectrum of disorders along the mTOR cascade. Novartis Found Smyp 288 : 260-272; discussion 272-281, 2007