{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:46:44Z","timestamp":1787028404921,"version":"build-2736575974"},"reference-count":166,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2018,5,16]],"date-time":"2018-05-16T00:00:00Z","timestamp":1526428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondo di Ateneo per la Ricerca di Base (FRB) 2015-Dept. of Chemistry, Biology and Biotechnology, University of Perugia","award":["D.D.n\u00b0126 21\/12\/2015"],"award-info":[{"award-number":["D.D.n\u00b0126 21\/12\/2015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The mechanistic target of rapamycin (mTOR), a serine-threonine kinase, plays a pivotal role in regulating cell growth and proliferation. Notably, a great deal of evidence indicates that mTOR signaling is also crucial in controlling proliferation and differentiation of several stem cell compartments. Consequently, dysregulation of the mTOR pathway is often associated with a variety of disease, such as cancer and metabolic and genetic disorders. For instance, hyperactivation of mTORC1 in neural stem cells (NSCs) is associated with the insurgence of neurological manifestation characterizing tuberous sclerosis complex (TSC). In this review, we survey the recent contributions of TSC physiopathology studies to understand the role of mTOR signaling in both neurogenesis and tumorigenesis and discuss how these new insights can contribute to developing new therapeutic strategies for neurological diseases and cancer.<\/jats:p>","DOI":"10.3390\/ijms19051474","type":"journal-article","created":{"date-parts":[[2018,5,17]],"date-time":"2018-05-17T03:49:29Z","timestamp":1526528969000},"page":"1474","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["mTOR Signaling and Neural Stem Cells: The Tuberous Sclerosis Complex Model"],"prefix":"10.3390","volume":"19","author":[{"given":"Alice","family":"Polchi","sequence":"first","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06122 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2750-6226","authenticated-orcid":false,"given":"Alessandro","family":"Magini","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06122 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danila Di","family":"Meo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06122 Perugia, Italy"},{"name":"Institute for Molecular Cell Biology, University of M\u00fcnster, Schlossplatz 5, 48149 M\u00fcnster, Germany"},{"name":"Cells-in-Motion Cluster of Excellence, University of M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brunella","family":"Tancini","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06122 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Emiliani","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06122 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"mTOR Signaling in Growth, Metabolism, and Disease","volume":"9","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ceb.2017.02.012","article-title":"mTORC1 signaling and the metabolic control of cell growth","volume":"45","author":"Manning","year":"2017","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_3","first-page":"3","article-title":"Tuberous sclerosis\u2014A model for tumour growth. Semin","volume":"52","author":"Dodd","year":"2016","journal-title":"Cell Dev. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.molcel.2012.06.009","article-title":"TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1","volume":"47","author":"Dibble","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1017\/S0012162206001058","article-title":"Tuberous sclerosis complex: Clinical features, diagnosis, and prevalence within Northern Ireland","volume":"48","author":"Devlin","year":"2006","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.neuron.2014.09.034","article-title":"The Neurology of mTOR","volume":"84","author":"Lipton","year":"2014","journal-title":"Neuron."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.neuroscience.2016.11.017","article-title":"Molecular neurobiology of mTOR","volume":"341","author":"Switon","year":"2017","journal-title":"Neuroscience"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.ceb.2011.09.003","article-title":"mTOR signaling in disease","volume":"23","author":"Dazert","year":"2011","journal-title":"Curr. Opin. Cell Bioi."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/onc.2009.352","article-title":"Common corruption of the mTOR signaling network in human tumors","volume":"27","author":"Menon","year":"2008","journal-title":"Oncogene"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1126\/science.aaa3870","article-title":"Architecture of human mTOR complex 1","volume":"351","author":"Aylett","year":"2016","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nature12122","article-title":"mTOR kinase structure, mechanism and regulation by the rapamycin-binding domain","volume":"497","author":"Yang","year":"2013","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.cell.2006.01.016","article-title":"TOR signaling in growth and metabolism","volume":"124","author":"Wullschleger","year":"2006","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR signaling in growth control and disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"ref_14","first-page":"79","article-title":"Growing knowledge of the mTOR signalling network. Semin","volume":"36","author":"Huang","year":"2014","journal-title":"Cell Dev. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yoon, M.S. (2017). The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling. Nutrients, 9.","DOI":"10.3390\/nu9111176"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15461","DOI":"10.1074\/jbc.C200665200","article-title":"The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif","volume":"278","author":"Nojima","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/S0960-9822(03)00329-4","article-title":"TOS motifmediated Raptor binding regulates 4E-BP1 multisite phosphorylation and function","volume":"13","author":"Schalm","year":"2003","journal-title":"Curr. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/nature25023","article-title":"Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40","volume":"552","author":"Yang","year":"2017","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"dev152595","DOI":"10.1242\/dev.152595","article-title":"mTOR signaling in stem and progenitor cells","volume":"145","author":"Meng","year":"2018","journal-title":"Development"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.molcel.2012.10.003","article-title":"Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1\/2 complex","volume":"49","author":"Kim","year":"2013","journal-title":"Mol. Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.devcel.2015.12.019","article-title":"WAC Regulates mTOR Activity by Acting as an Adaptor for the TTT and Pontin\/Reptin Complexes","volume":"36","author":"Xu","year":"2016","journal-title":"Dev. Cell."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.tibs.2013.01.004","article-title":"Nutrient signaling to mTOR and cell growth","volume":"38","author":"Jewell","year":"2013","journal-title":"Trends Biochem. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7082696","DOI":"10.1155\/2017\/7082696","article-title":"mTOR-Dependent Cell Proliferation in the Brain","volume":"2017","author":"Ryskalin","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Paquette, M., El-Houjeiri, L., and Pause, A. (2018). mTOR Pathways in Cancer and Autophagy. Cancers (Basel), 10.","DOI":"10.3390\/cancers10010018"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Tee, A.R. (2018). The Target of Rapamycin and Mechanisms of Cell Growth. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030880"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/ncb2763","article-title":"Signal integration by mTORC1 coordinates nutrient input with biosynthetic output","volume":"15","author":"Dibble","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.cell.2013.11.049","article-title":"Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome","volume":"156","author":"Menon","year":"2014","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1083\/jcb.200507119","article-title":"Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning","volume":"173","author":"Cai","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.cell.2005.02.031","article-title":"Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis","volume":"121","author":"Ma","year":"2005","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13489","DOI":"10.1073\/pnas.0405659101","article-title":"Tumorpromoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase","volume":"101","author":"Roux","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.molcel.2008.03.003","article-title":"AMPK phosphorylation of raptor mediates a metabolic checkpoint","volume":"30","author":"Gwinn","year":"2008","journal-title":"Mol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/j.cell.2006.06.055","article-title":"TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth","volume":"126","author":"Inoki","year":"2006","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/nrm3757","article-title":"Making new contacts: The mTOR network in metabolism and signalling crosstalk","volume":"15","author":"Shimobayashi","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1038\/ncb2822","article-title":"A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS","volume":"15","author":"Zhang","year":"2013","journal-title":"Nat Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"33076","DOI":"10.1074\/jbc.M507201200","article-title":"hVps34 is a nutrientregulated lipid kinase required for activation of p70 S6 kinase","volume":"280","author":"Byfield","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"14238","DOI":"10.1073\/pnas.0506925102","article-title":"Amino acids mediate mTOR\/Raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase","volume":"102","author":"Nobukuni","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"18717","DOI":"10.1074\/jbc.M414499200","article-title":"The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses","volume":"280","author":"Smith","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1126\/science.1157535","article-title":"The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1","volume":"320","author":"Sancak","year":"2008","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/ncb1753","article-title":"Regulation of TORC1 by Rag GTPases in nutrient response","volume":"10","author":"Kim","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.cell.2010.02.024","article-title":"Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids","volume":"141","author":"Sancak","year":"2010","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1126\/science.1232044","article-title":"A tumor suppressor complex with GAP activity for the RagGTPases that signal amino acid sufficiency to mTORC1","volume":"340","author":"Chantranupong","year":"2013","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Demetriades, C., Doumpas, N., and Teleman, A.A. (2014). Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell, 156.","DOI":"10.1016\/j.cell.2014.01.024"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1126\/science.1259472","article-title":"Metabolism. Differential regulation of mTORC1 by leucine and glutamine","volume":"347","author":"Jewell","year":"2015","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/j.cmet.2013.10.001","article-title":"mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation","volume":"18","author":"Morita","year":"2013","journal-title":"Cell Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nrm2672","article-title":"Molecular mechanisms of mTOR-mediated translational control","volume":"10","author":"Ma","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1101\/gad.13.11.1422","article-title":"Regulation of 4E-BP1 phosphorylation: A novel two-step mechanism","volume":"13","author":"Gingras","year":"1999","journal-title":"Genes Dev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1073\/pnas.95.4.1432","article-title":"RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1","volume":"95","author":"Burnett","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/onc.2012.606","article-title":"Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptionalprogram","volume":"33","author":"Chauvin","year":"2014","journal-title":"Oncogene"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.lfs.2015.03.001","article-title":"The S6K protein family in health and disease","volume":"131","author":"Tavares","year":"2015","journal-title":"Life Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"42890","DOI":"10.1074\/jbc.M112.404822","article-title":"Role of p70S6K1-mediated phosphorylation of eIF4B and PDCD4 proteins in the regulation of protein synthesis","volume":"287","author":"Dennis","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4370","DOI":"10.1093\/emboj\/20.16.4370","article-title":"Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase","volume":"20","author":"Wang","year":"2001","journal-title":"EMBO J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1016\/j.cub.2004.08.061","article-title":"SKAR is a specific target of S6 kinase 1 in cell growth control","volume":"14","author":"Richardson","year":"2004","journal-title":"Curr. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.cell.2008.02.031","article-title":"SKAR links pre-mRNA splicing to mTOR\/S6K1-mediated enhanced translation efficiency of spliced mRNAs","volume":"133","author":"Ma","year":"2008","journal-title":"Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1126\/science.1228792","article-title":"Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1","volume":"339","author":"Howell","year":"2013","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1126\/science.1228771","article-title":"Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis","volume":"339","author":"Robitaille","year":"2013","journal-title":"Science"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1126\/science.aad0489","article-title":"mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle","volume":"351","author":"Hoxhaj","year":"2016","journal-title":"Science"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1101\/sqb.2002.67.491","article-title":"SREBPs: Transcriptional mediators of lipid homeostasis","volume":"67","author":"Horton","year":"2002","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.molcel.2010.06.022","article-title":"Activation of a metabolic gene regulatory network downstream of mTOR complex 1","volume":"39","author":"Yecies","year":"2010","journal-title":"Mol. Cell."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S1474-4422(15)00069-1","article-title":"Neurological and neuropsychiatric aspects of tuberous sclerosis complex","volume":"14","author":"Curatolo","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.yebeh.2007.07.010","article-title":"Psychiatric comorbid conditions in a clinic population of 241 patients with tuberous sclerosis complex","volume":"11","author":"Muzykewicz","year":"2007","journal-title":"Epilepsy Behav."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1126\/science.277.5327.805","article-title":"Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34","volume":"277","author":"Hermans","year":"1997","journal-title":"Science"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"European Chromosome 16 Tuberous Sclerosis Consortium (1993). Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell, 75, 1305\u20131315.","DOI":"10.1016\/0092-8674(93)90618-Z"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1093\/hmg\/ddq491","article-title":"Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex","volume":"20","author":"Zeng","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1136\/jmedgenet-2013-101680","article-title":"Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly","volume":"50","author":"Tcherkezian","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1002\/humu.22529","article-title":"TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease","volume":"35","author":"Alfaiz","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_66","first-page":"1185","article-title":"Timing of mTOR activation affects tuberous sclerosis complex neuropathology in mouse models","volume":"6","author":"Magri","year":"2013","journal-title":"Dis. Models Mech."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"ENEURO.0046-15.2015","DOI":"10.1523\/ENEURO.0046-15.2015","article-title":"Complex Neurological Phenotype in Mutant Mice Lacking Tsc2 in Excitatory Neurons of the Developing Forebrain","volume":"2","author":"Crowell","year":"2015","journal-title":"eNeuro."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.stem.2011.09.008","article-title":"Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions","volume":"9","author":"Magri","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3303","DOI":"10.1093\/hmg\/ddx214","article-title":"TFEB activation restores migration ability to Tsc1-deficient adult neural stem\/progenitor cells","volume":"26","author":"Magini","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4286","DOI":"10.1093\/hmg\/dds262","article-title":"Graded loss of tuberin in an allelic series of brain models of TSC correlates with survival, and biochemical, histological and behavioural features","volume":"21","author":"Yuan","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Palavra, F., Robal, C., and Reis, F. (2017). Recent Advances and Challenges of mTOR Inhibitors Use in the Treatment of Patients with Tuberous Sclerosis Complex. Oxid. Med. Cell. Longev.","DOI":"10.1155\/2017\/9820181"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s40265-016-0552-9","article-title":"The Role of mTOR Inhibitors in the Treatment of Patients with Tuberous Sclerosis Complex: Evidence-based and Expert Opinions","volume":"76","author":"Curatolo","year":"2016","journal-title":"Drugs"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/emmm.201100131","article-title":"Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis","volume":"3","author":"Neuman","year":"2011","journal-title":"EMBO Mol. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"14534","DOI":"10.1038\/srep14534","article-title":"PAK2 is an effector of TSC1\/2 signaling independent of mTOR and a potential therapeutic target for tuberous sclerosis complex","volume":"5","author":"Alves","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"5155","DOI":"10.1038\/srep05155","article-title":"Activation of Rheb, but not of mTORC1, impairs spine synapse morphogenesis in tuberous sclerosis complex","volume":"4","author":"Yasuda","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"6842","DOI":"10.1038\/ncomms7842","article-title":"Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex","volume":"6","author":"Sugiura","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"6243","DOI":"10.1093\/nar\/gku278","article-title":"Evidence that TSC2 acts as a transcription factor and binds to and represses the promoter of Epiregulin","volume":"42","author":"Pradhan","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s13073-016-0347-3","article-title":"Genomic analysis of the molecular neuropathology of tuberous sclerosis using a human stem cell model","volume":"8","author":"Grabole","year":"2016","journal-title":"Genome Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1067\/mjd.2002.120530","article-title":"Tuberous sclerosis-associated lesions of the kidney, brain, and skin are angiogenic neoplasms","volume":"46","author":"Arbiser","year":"2002","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Rad, E., Murray, J.T., and Tee, A.R. (2018). Oncogenic Signaling through Mechanistic Target of Rapamycin (mTOR): A Driver of Metabolic Transformation and Cancer Progression. Cancers (Basel), 10.","DOI":"10.3390\/cancers10010005"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nature10912","article-title":"The translational landscape of mTOR signalling steers cancer initiation and metastasis","volume":"485","author":"Hsieh","year":"2012","journal-title":"Nature"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1101\/gad.1314605","article-title":"Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2","volume":"19","author":"Manning","year":"2005","journal-title":"Genes Dev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"6107","DOI":"10.1158\/0008-5472.CAN-09-0975","article-title":"Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors","volume":"69","author":"Huang","year":"2009","journal-title":"Cancer Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"54858","DOI":"10.18632\/oncotarget.18963","article-title":"Hyperactivated mTORC1 downregulation of FOXO3a\/PDGFR\u03b1\/AKT cascade restrains tuberous sclerosis complex-associated tumor development","volume":"8","author":"Wang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"28435","DOI":"10.18632\/oncotarget.8633","article-title":"mTORC1-mediated downregulation of COX2 restrains tumor growth caused by TSC2 deficiency","volume":"7","author":"Li","year":"2016","journal-title":"Oncotarget"},{"key":"ref_86","first-page":"407","article-title":"Deficient TSC1\/TSC2-complex suppression of SOX9-osteopontin-AKT signalling cascade constrains tumour growth in tuberous sclerosis complex","volume":"26","author":"Jin","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1172\/JCI96342","article-title":"Tuberous sclerosis complex-associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt","volume":"128","author":"Zordan","year":"2018","journal-title":"J. Clin. Invest."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1002\/glia.22983","article-title":"Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and the irregulation in human astrocytes and SEGA-derived cell cultures","volume":"64","author":"Iyer","year":"2016","journal-title":"Glia"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"64714","DOI":"10.18632\/oncotarget.19947","article-title":"Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells","volume":"8","author":"Lam","year":"2017","journal-title":"Oncotarget"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/path.4176","article-title":"TSC1 involvement in bladder cancer: Diverse effects and therapeutic implications","volume":"230","author":"Guo","year":"2013","journal-title":"J. Pathol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"6008","DOI":"10.1158\/1078-0432.CCR-09-0898","article-title":"Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer","volume":"15","author":"Platt","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1158\/1535-7163.MCT-14-0768","article-title":"Loss of tuberous sclerosis complex 2 (TSC2) is frequent in hepatocellular carcinoma and predicts response to mTORC1 inhibitor everolimus","volume":"14","author":"Huynh","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1126\/science.1200609","article-title":"DAXX\/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors","volume":"331","author":"Jiao","year":"2011","journal-title":"Science"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1093\/nar\/gkq929","article-title":"COSMIC: Mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer","volume":"39","author":"Forbes","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_95","first-page":"157","article-title":"Mammalian Target of Rapamycin: Its Role in Early Neural Development and in Adult and Aged Brain Function","volume":"10","author":"Gonsebatt","year":"2016","journal-title":"Front. Cell Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1152\/physrev.00038.2014","article-title":"mTOR in Brain Physiology and Pathologies","volume":"95","author":"Bockaert","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"9508","DOI":"10.1128\/MCB.24.21.9508-9516.2004","article-title":"Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development","volume":"24","author":"Gangloff","year":"2004","journal-title":"Mol. Cell Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"7799","DOI":"10.1523\/JNEUROSCI.3294-12.2013","article-title":"Inactivation of mTORC1 in the developing brain causes microcephaly and affects gliogenesis","volume":"33","author":"Cloetta","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.celrep.2013.09.017","article-title":"mTORC1 targets the translational repressor 4E-BP2, but not S6 kinase 1\/2, to regulate neural stem cell self-renewal in vivo","volume":"5","author":"Hartman","year":"2013","journal-title":"Cell Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.neulet.2015.12.042","article-title":"Switching on mTORC1 induces neurogenesis but not proliferation in neural stem cells of young mice","volume":"614","author":"Mahoney","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1093\/hmg\/ddr511","article-title":"Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell Tsc1 deletion","volume":"21","author":"Feliciano","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1101\/gad.16750211","article-title":"Tsc1 mutant neural stem\/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle","volume":"25","author":"Zhou","year":"2011","journal-title":"Genes Dev."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.1523\/JNEUROSCI.1840-12.2013","article-title":"Rheb activation in subventricular zone progenitors leads to heterotopia, ectopic neuronal differentiation, and rapamycin-sensitive olfactory micronodules and dendrite hypertrophy of newborn neurons","volume":"33","author":"Lafourcade","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1093\/cercor\/bhr300","article-title":"GABAergic interneuron development and function is modulated by the Tsc1 gene","volume":"22","author":"Fu","year":"2012","journal-title":"Cereb. Cortex"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"3186","DOI":"10.1523\/JNEUROSCI.4011-10.2011","article-title":"RTP801\/REDD1 regulates the timing of cortical neurogenesis and neuron migration","volume":"31","author":"Malagelada","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1016\/j.celrep.2014.04.048","article-title":"Selective activation of mTORC1 signaling recapitulates microcephaly, tuberous sclerosis, and neurodegenerative diseases","volume":"7","author":"Kassai","year":"2014","journal-title":"Cell Rep."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"4076","DOI":"10.1242\/dev.108282","article-title":"mTOR regulates brain morphogenesis by mediating GSK3 signaling","volume":"141","author":"Ka","year":"2014","journal-title":"Development"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1002\/dneu.22392","article-title":"mTOR kinase is needed for the development and stabilization of dendritic arbors in newly born olfactory bulb neurons","volume":"76","author":"Skaecka","year":"2016","journal-title":"Dev. Neurobiol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1002\/ana.21331","article-title":"Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex","volume":"63","author":"Zeng","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.neuron.2013.03.030","article-title":"Temporal and mosaic Tsc1 deletion in the developing thalamus disrupts thalamocortical circuitry, neural function, and behavior","volume":"78","author":"Normand","year":"2013","journal-title":"Neuron."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1038\/ncomms2295","article-title":"Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex","volume":"3","author":"Sato","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/nm1788","article-title":"Reversal of learning deficits in a Tsc2+\/\u2212 mouse model of tuberous sclerosis","volume":"14","author":"Ehninger","year":"2008","journal-title":"Nat. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1002\/ana.23943","article-title":"TORC1-dependent epilepsy caused by acute biallelic Tsc1 deletion in adult mice","volume":"74","author":"Abs","year":"2013","journal-title":"Ann. Neurol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1111\/epi.13923","article-title":"Postnatal reduction of tuberous sclerosis complex 1 expression in astrocytes and neurons causes seizures in an age-dependent manner","volume":"58","author":"Zou","year":"2017","journal-title":"Epilepsia"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1016\/j.neuron.2012.08.002","article-title":"Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy","volume":"75","author":"Pun","year":"2012","journal-title":"Neuron"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1111\/epi.12946","article-title":"mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia","volume":"56","author":"Nguyen","year":"2015","journal-title":"Epilepsia"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.nbd.2017.08.014","article-title":"PTEN deletion increases hippocampal granule cell excitability in male and female mice","volume":"108","author":"Santos","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.pbb.2015.05.022","article-title":"Rapamycin suppresses PTZ-induced seizures at different developmental stages of zebrafish","volume":"139","author":"Siebel","year":"2015","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"9056","DOI":"10.1523\/JNEUROSCI.3870-12.2013","article-title":"PI3K-Akt signaling activates mTOR-mediated epileptogenesis in organotypic hippocampal culture model of post-traumatic epilepsy","volume":"33","author":"Berdichevsky","year":"2013","journal-title":"J. Neurosci"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1111\/j.1528-1167.2011.03384.x","article-title":"Pentylenetetrazole-induced seizures cause acute, but not chronic, mTOR pathway activation in rat","volume":"53","author":"Zhang","year":"2012","journal-title":"Epilepsia"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.nbd.2012.10.014","article-title":"Loss of Tsc2 in Purkinje cells is associated with autistic-like behaviour in a mouse model of tuberous sclerosis complex","volume":"51","author":"Reith","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/nature11310","article-title":"Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice","volume":"488","author":"Tsai","year":"2012","journal-title":"Nature"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/nature11628","article-title":"Autism related deficits via dysregulated eIF4E-dependent translational control","volume":"493","author":"Gkogkas","year":"2013","journal-title":"Nature"},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Magdalon, J., S\u00e1nchez-S\u00e1nchez, S.M., Griesi-Oliveira, K., and Serti\u00e9, A.L. (2017). Dysfunctional mTORC1 Signaling: A Convergent Mechanism between Syndromic and Nonsyndromic Forms of Autism Spectrum Disorder? Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030659"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1080\/14737175.2018.1428562","article-title":"mTOR dysregulation and tuberous sclerosis-related epilepsy","volume":"18","author":"Curatolo","year":"2018","journal-title":"Expert Rev. Neurother."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Spilman, P., Podlutskaya, N., Hart, M.J., Debnath, J., Gorostiza, O., Bredesen, D., Richardson, A., Strong, R., and Galvan, V. (2010). Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer\u2019s disease. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009979"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"7988","DOI":"10.1523\/JNEUROSCI.0777-14.2014","article-title":"Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer\u2019s disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature","volume":"34","author":"Caccamo","year":"2014","journal-title":"J Neurosci."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Crews, L., Spencer, B., Desplats, P., Patrick, C., Paulino, A., Rockenstein, E., Hansen, L., Adame, A., Galasko, D., and Masliah, E. (2010). Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009313"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1111\/j.1471-4159.2011.07435.x","article-title":"Induction of autophagy with catalytic mTOR inhibitors reduces huntingtin aggregates in a neuronal cell model","volume":"119","author":"Roscic","year":"2011","journal-title":"J Neurochem."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/nrneurol.2016.81","article-title":"The mTOR signaling cascade: Paving new roads to cure neurological disease","volume":"12","author":"Crino","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13023-017-0596-2","article-title":"mTOR inhibitors in the pharmacologic management of tuberous sclerosis complex and their potential role in other rare neurodevelopmental disorders","volume":"12","author":"Franz","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nature08221","article-title":"Rapamycin fed late in life extends lifespan in genetically heterogeneous mice","volume":"460","author":"Harrison","year":"2009","journal-title":"Nature"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1111\/acel.12194","article-title":"Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction","volume":"13","author":"Miller","year":"2014","journal-title":"Aging Cell"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1182\/blood-2010-05-287821","article-title":"Constitutive reductions in mTOR alter cell size, immune cell development, and antibody production","volume":"117","author":"Zhang","year":"2011","journal-title":"Blood"},{"key":"ref_135","first-page":"1","article-title":"Extending lifespan through autophagy stimulation: A future perspective","volume":"65","author":"Tancini","year":"2017","journal-title":"J. Gerontology Geriatrics"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"721","DOI":"10.7164\/antibiotics.28.721","article-title":"Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle","volume":"28","author":"Kudelski","year":"1975","journal-title":"J Antibiot. (Tokyo)"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1517\/14656566.6.3.479","article-title":"Sirolimus: A new option in transplantation","volume":"6","author":"Mota","year":"2005","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"17414","DOI":"10.1073\/pnas.0809136105","article-title":"Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation","volume":"105","author":"Choo","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Xie, J., Wang, X., and Proud, C.G. (2016). mTOR inhibitors in cancer therapy. F1000Res, 5.","DOI":"10.12688\/f1000research.9207.1"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1126\/science.1215135","article-title":"Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity","volume":"335","author":"Lamming","year":"2012","journal-title":"Science"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1002\/ana.20784","article-title":"Rapamycin causes regression of astrocytomas in tuberous sclerosis complex","volume":"59","author":"Franz","year":"2006","journal-title":"Ann Neurol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1038\/aps.2015.68","article-title":"Toward rapamycin analog (rapalog)-based precision cancer therapy","volume":"36","author":"Meng","year":"2015","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0140-6736(12)61134-9","article-title":"Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): A multicentre, randomised, placebo-controlled phase 3 trial","volume":"381","author":"Franz","year":"2013","journal-title":"Lancet"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/S0140-6736(12)61767-X","article-title":"Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): A multicentre, randomised, double-blind, placebo-controlled trial","volume":"381","author":"Bissler","year":"2013","journal-title":"Lancet"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s00467-017-3806-1","article-title":"The effect of everolimus on renal angiomyolipoma in pediatric patients with tuberous sclerosis being treated for subependymal giant cell astrocytoma","volume":"33","author":"Bissler","year":"2018","journal-title":"Pediatr. Nephrol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1002\/acn3.494","article-title":"Everolimus for treatment of tuberous sclerosis complex-associated neuropsychiatric disorders","volume":"4","author":"Krueger","year":"2017","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1212\/WNL.0000000000003400","article-title":"Long-term treatment of epilepsy with everolimus in tuberous sclerosis","volume":"87","author":"Krueger","year":"2016","journal-title":"Neurology."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1056\/NEJMoa1001671","article-title":"Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis","volume":"363","author":"Krueger","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1002\/ana.24523","article-title":"Everolimus for subependymal giant cell astrocytoma: 5-Year final analysis","volume":"78","author":"Franz","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_150","first-page":"CD011272","article-title":"Rapamycin and rapalogs for tuberous sclerosis complex","volume":"7","author":"Sasongko","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_151","first-page":"241","article-title":"New inhibitors of the PI3K-Akt-mTOR pathway: Insights into mTOR signaling from a new generation of tor kinase domain inhibitors (TORKinibs)","volume":"347","author":"Feldmanand","year":"2010","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1200\/JCO.2007.14.5482","article-title":"Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: A phase I tumor pharmacodynamic study in patients with advanced solid tumors","volume":"26","author":"Tabernero","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"555","DOI":"10.7150\/jca.17205","article-title":"Combined Targeting of mTOR and Akt Using Rapamycin and MK-2206 in The Treatment of Tuberous Sclerosis Complex","volume":"8","author":"Ji","year":"2017","journal-title":"J Cancer."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1158\/1535-7163.MCT-08-0017","article-title":"Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase\/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity","volume":"7","author":"Maira","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1021\/ml900028r","article-title":"Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin","volume":"1","author":"Knight","year":"2010","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/nature17963","article-title":"Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor","volume":"534","author":"Okaniwa","year":"2016","journal-title":"Nature,"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1158\/1541-7786.MCR-13-0258-T","article-title":"Autophagy-dependent metabolic reprogramming sensitizes TSC2-deficient cells to the antimetabolite 6-aminonicotinamide","volume":"12","author":"Parkhitko","year":"2014","journal-title":"Mol. Cancer Res."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"371","DOI":"10.4161\/cc.27355","article-title":"Resveratrol prevents rapamycin-induced upregulation of autophagy and selectively induces apoptosis in TSC2-deficient cells","volume":"3","author":"Alayev","year":"2014","journal-title":"Cell Cycle."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1165\/rcmb.2015-0022OC","article-title":"Effects of combining rapamycin and resveratrol on apoptosis and growth of TSC2-deficient xenograft tumors","volume":"53","author":"Alayev","year":"2015","journal-title":"Am J Respir Cell Mol. Biol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1084\/jem.20140341","article-title":"Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex","volume":"211","author":"Liang","year":"2014","journal-title":"J. Exp. Med."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s40478-015-0225-z","article-title":"Tuberous sclerosis complex neuropathology requires glutamate-cysteine ligase","volume":"3","author":"Malik","year":"2015","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1002\/iub.1579","article-title":"Tuberous sclerosis complex: From molecular biology to novel therapeutic approaches","volume":"68","author":"Switon","year":"2016","journal-title":"IUBMB Life"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"3255","DOI":"10.1158\/0008-5472.CAN-16-2458","article-title":"p62\/SQSTM1 cooperates with hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis","volume":"77","author":"Lam","year":"2017","journal-title":"Cancer Res."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.neuron.2014.09.009","article-title":"MEK-ERK1\/2-dependent FLNA overexpression promotes abnormal dendritic patterning in tuberous sclerosis independent of mTOR","volume":"84","author":"Zhang","year":"2014","journal-title":"Neuron"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.celrep.2015.07.013","article-title":"Impaired reelin-Dab1 signaling contributes to neuronal migration deficits of tuberous sclerosis complex","volume":"12","author":"Moon","year":"2015","journal-title":"Cell Rep."},{"key":"ref_166","unstructured":"Dolcetta, D., Giovagnoli, S., Cassano, T., and Emiliani, C. (2015). Intrathecal administration of mTOR inhibitors for the therapy of neurodegenerative, neuroinflammatory and neurooncologic diseases. (Application No. US20150132397A1), U.S. Patent."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/5\/1474\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:04:28Z","timestamp":1760195068000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/5\/1474"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,16]]},"references-count":166,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2018,5]]}},"alternative-id":["ijms19051474"],"URL":"https:\/\/doi.org\/10.3390\/ijms19051474","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,16]]}}}