Abstract

Mammalian target of rapamycin (mTor) plays multiple role in central nervous system and is involved in regulation of cell viability, differentiation, transcription, translation, protein degradation, actin cytoskeletal organization and autophagy. Recent experimental and clinical studies reveal that disturbances of mTOR signaling are involved in the pathogenesis of autism spectrum disorders (ASD). This article reviews current data on the alteration in the mTOR transduction cascade, which may contribute to common neurobehavioral disorders typical for ASD. Moreover, the results of the latest experimental studies on the potential of mTOR inhibitors for the treatment of ASD are reviewed.

References

• 1. American Psychiatric Association. Diagnostic and statistical manualof mental disorders, 4th ed., text revision. Washington, DC:American Psychiatric Association, 2000
  Google Scholar
• 2. Asano E., Chugani D.C., Muzik O., Behen M., Janisse J., RothermelR., Mangner T.J., Chakraborty P.K., Chugani H.T.: Autism in tuberoussclerosis complex is related to both cortical and subcortical dysfunction.Neurology, 2001; 57: 1269-1277
  Google Scholar
• 3. Asato M.R., Hardan A.Y.: Neuropsychiatric problems in tuberoussclerosis complex. J. Child Neurol., 2004; 19: 241-249
  Google Scholar
• 4. Avruch J., Lin Y., Long X., Murthy S., Ortiz-Vega S.: Recent advancesin the regulation of the TOR pathway by insulin and nutrients.Curr. Opin. Clin. Nutr. Metab. Care, 2005; 8: 67-72
  Google Scholar
• 5. Bailey A., Le Couteur A., Gottesman I., Bolton P., Simonoff E.,Yuzda E., Rutter M.: Autism as a strongly genetic disorder: evidencefrom a British twin study. Psychol. Med., 1995; 25: 63-77
  Google Scholar
• 6. Bassell G.J., Warren S.T.: Fragile X syndrome: loss of local mRNAregulation alters synaptic development and function. Neuron, 2008;60: 201-214
  Google Scholar
• 7. Bear M.F., Huber K.M., Warren S.T.: The mGluR theory of fragileX mental retardation. Trends Neurosci., 2004; 27: 370-377
  Google Scholar
• 8. Bolton P.F., Griffiths P.D.: Association of tuberous sclerosis oftemporal lobes with autism and atypical autism. Lancet, 1997; 349:392-395
  Google Scholar
• 9. Bryson S.E., Rogers S.J., Fombonne E.: Autism spectrum disorders:early detection, intervention, education, and psychopharmacologicalmanagement. Can. J. Psychiatry, 2003; 48: 506-516
  Google Scholar
• 10. Butler M.G., Dasouki M.J., Zhou X.P., Talebizadeh Z., Brown M.,Takahashi T.N., Miles J.H., Wang C.H., Stratton R., Pilarski R., Eng C.:Subset of individuals with autism spectrum disorders and extrememacrocephaly associated with germline PTEN tumour suppressorgene mutations. J. Med. Genet., 2005; 42: 318-321
  Google Scholar
• 11. Chen J., Zheng X.F., Brown E.J., Schreiber S.L.: Identification ofan 11-kDa FKBP12-rapamycin-binding domain within the 289-kDaFKBP12-rapamycin-associated protein and characterization of a criticalserine residue. Proc. Natl. Acad. Sci. USA, 1995; 92: 4947-4951
  Google Scholar
• 12. Choo A.Y., Yoon S.O., Kim S.G., Roux P.P., Blenis J.: Rapamycindifferentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specificrepression of mRNA translation. Proc. Natl. Acad. Sci. USA, 2008;105: 17414-17419
  Google Scholar
• 13. Chu E.C., Tarnawski A.S.: PTEN regulatory functions in tumorsuppression and cell biology. Med. Sci. Monit., 2004; 10: RA235-RA241
  Google Scholar
• 14. Codogno P., Meijer A.J.: Autophagy and signaling: their rolein cell survival and cell death. Cell Death Differ., 2005; 12 (Suppl.2): 1509-1518
  Google Scholar
• 15. Costa R.M., Federov N.B., Kogan J.H., Murphy G.G., Stern J., Ohno M.,Kucherlapati R., Jacks T., Silva A.J.: Mechanism for the learning deficits ina mouse model of neurofibromatosis type 1. Nature, 2002; 415: 526-530
  Google Scholar
• 16. Crino P.B., Nathanson K.L., Henske E.P.: The tuberous sclerosiscomplex. N. Engl. J. Med., 2006; 355: 1345-1356
  Google Scholar
• 17. Dan H.C., Sun M., Yang L., Feldman R.I., Sui X.M., Ou C.C., NellistM., Yeung R.S., Halley D.J., Nicosia S.V., Pledger W.J., Cheng J.Q.: Phosphatidylinositol3-kinase/Akt pathway regulates tuberous sclerosistumor suppressor complex by phosphorylation of tuberin. J. Biol.Chem., 2002; 277: 35364-35370
  Google Scholar
• 18. de Vries P.J.: Targeted treatments for cognitive and neurodevelopmentaldisorders in tuberous sclerosis complex. Neurotherapeutics,2010; 7: 275-282
  Google Scholar
• 19. Ehninger D., Han S., Shilyansky C., Zhou Y., Li W., KwiatkowskiD.J., Ramesh V., Silva A.J.: Reversal of learning deficits in a Tsc2+/-mouse model of tuberous sclerosis. Nat. Med., 2008; 14: 843-848
  Google Scholar
• 20. Ehninger D., Silva A.J.: Rapamycin for treating tuberous sclerosisand autism spectrum disorders. Trends Mol. Med., 2011; 17: 78-87
  Google Scholar
• 21. Eng C.: Will the real Cowden syndrome please stand up: reviseddiagnostic criteria. J. Med. Genet., 2000; 37: 828-830
  Google Scholar
• 22. Fingar D.C., Blenis J.: Target of rapamycin (TOR): an integratorof nutrient and growth factor signals and coordinator of cell growthand cell cycle progression. Oncogene, 2004; 23: 3151–3171
  Google Scholar
• 23. Fombonne E.: The prevalence of autism. JAMA, 2003; 289: 87-89
  Google Scholar
• 24. Fombonne E.: Epidemiological surveys of autism and other pervasivedevelopmental disorders: an update. J. Autism Dev. Disord.,2003; 33: 365-382
  Google Scholar
• 25. Frias M.A., Thoreen C.C., Jaffe J.D., Schroder W., Sculley T., CarrS.A., Sabatini D.M.: mSin1 is necessary for Akt/PKB phosphorylation,and its isoforms define three distinct mTORC2s. Curr. Biol.,2006; 16: 1865-1870
  Google Scholar
• 26. Gawęda A., Janas Kozik M.: Autyzm w rozumieniu teorii umysłu.Neuroscience Fakty, 2012; 3: 40-47
  Google Scholar
• 27. Geschwind D.H., Levitt P.: Autism spectrum disorders: developmentaldisconnection syndromes. Curr. Opin. Neurobiol., 2007;17: 103-111
  Google Scholar
• 28. Goorden S.M., van Woerden G.M., van der Weerd L., Cheadle J.P.,Elgersma Y.: Cognitive deficits in Tsc1+/- mice in the absence of cerebrallesions and seizures. Ann. Neurol., 2007; 62: 648-655
  Google Scholar
• 29. Gross C., Berry-Kravis E.M., Bassell G.J.: Therapeutic strategiesin fragile X syndrome: dysregulated mGluR signaling and beyond.Neuropsychopharmacology, 2012; 37: 178-195
  Google Scholar
• 30. Hagerman R.J., Hagerman P.J.: The fragile X premutation: intothe phenotypic fold. Curr. Opin. Genet. Dev., 2002; 12: 278-283
  Google Scholar
• 31. Hara K., Maruki Y., Long X., Yoshino K., Oshiro N., Hidayat S., TokunagaC., Avruch J., Yonezawa K.: Raptor, a binding partner of targetof rapamycin (TOR), mediates TOR action. Cell, 2002; 110: 177-189
  Google Scholar
• 32. Harris T.E., Lawrence J.C.Jr.: TOR signaling. Sci STKE, 2003; 2003:re15
  Google Scholar
• 33. Huang S., Bjornsti M.A., Houghton P.J.: Rapamycins: mechanismof action and cellular resistance. Cancer Biol. Ther., 2003; 2: 222-232
  Google Scholar
• 34. Hyman S.L., Shores A., North K.N.: The nature and frequency ofcognitive deficits in children with neurofibromatosis type 1. Neurology,2005; 65: 1037-1044
  Google Scholar
• 35. Jefferies H.B., Reinhard C., Kozma S.C., Thomas G.: Rapamycinselectively represses translation of the “polypyrimidine tract” mRNAfamily. Proc. Natl. Acad. Sci. USA, 1994; 91: 4441-4445
  Google Scholar
• 36. Jin P., Warren S.T.: New insights into fragile X syndrome: frommolecules to neurobehaviors. Trends Biochem. Sci., 2003; 28: 152-158
  Google Scholar
• 37. Johannessen C.M., Reczek E.E., James M.F., Brems H., Legius E.,Cichowski K.: The NF1 tumor suppressor critically regulates TSC2and mTOR. Proc. Natl. Acad. Sci. USA, 2005; 102: 8573-8578
  Google Scholar
• 38. Jóźwiak P, Lipińska A.: Rola transportera glukozy 1 (GLUT1)w diagnostyce i terapii nowotworów. Postępy Hig. Med. Dośw., 2012;66: 165-174
  Google Scholar
• 39. Kanner L.: Autistic disturbances of affective contact. Nerv. Child,1943; 2: 217-250
  Google Scholar
• 40. Keith C.T., Schreiber S.L.: PIK-related kinases: DNA repair, recombination,and cell cycle checkpoints. Science, 1995; 270: 50-51
  Google Scholar
• 41. Kim D.H., Sarbassov D.D., Ali S.M., King J.E., Latek R.R., Erdjument-BromageH., Tempst P., Sabatini D.M.: mTOR interacts withraptor to form a nutrient-sensitive complex that signals to the cellgrowth machinery. Cell, 2002; 110: 163-175
  Google Scholar
• 42. Kim D.H., Sarbassov D.D., Ali S.M., Latek R.R., Guntur K.V., Erdjument-BromageH., Tempst P., Sabatini D.M.: GβL, a positive regulatorof the rapamycin-sensitive pathway required for the nutrient-sensitiveinteraction between raptor and mTOR. Mol. Cell,2003; 11: 895-904
  Google Scholar
• 43. Kirchner G.I., Meier-Wiedenbach I., Manns M.P.: Clinical pharmacokineticsof everolimus. Clin. Pharmacokinet., 2004; 43: 83-95
  Google Scholar
• 44. Kost A., Kasprowska D., Labuzek K., Wiaderkiewicz R., GabryelB.: Autofagia w niedokrwieniu mózgu. Postępy Hig. Med. Dośw.,2011; 65: 524-533
  Google Scholar
• 45. Kumar R.A., Christian S.L.: Genetics of autism spectrum disorders.Curr. Neurol. Neurosci. Rep., 2009; 9: 188-197
  Google Scholar
• 46. Kumar V., Zhang M.X., Swank M.W., Kunz J., Wu G.Y.: Regulationof dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPKsignaling pathways. J. Neurosci., 2005; 25: 11288-11299
  Google Scholar
• 47. Kwon C.H., Luikart B.W., Powell C.M., Zhou J., Matheny S.A.,Zhang W., Li Y., Baker S.J., Parada L.F.: Pten regulates neuronal arborizationand social interaction in mice. Neuron, 2006; 50: 377-388
  Google Scholar
• 48. Lachlan K.L., Lucassen A.M., Bunyan D., Temple I.K.: Cowdensyndrome and Bannayan-Riley-Ruvalcaba syndrome represent onecondition with variable expression and age-related penetrance: resultsof a clinical study of PTEN mutation carriers. J. Med. Genet.,2007; 44: 579-585
  Google Scholar
• 49. Lainhart J.E., Bigler E.D., Bocian M., Coon H., Dinh E., Dawson G.,Deutsch C.K., Dunn M., Estes A., Tager-Flusberg H., Folstein S., HepburnS., Hyman S., McMahon W., Minshew N. i wsp.: Head circumferenceand height in autism: a study by the Collaborative Programof Excellence in Autism. Am. J. Med. Genet. A, 2006; 140: 2257-2274
  Google Scholar
• 50. Laycock-van Spyk S., Thomas N., Cooper D.N., Upadhyaya M.:Neurofibromatosis type 1-associated tumours: their somatic mutationalspectrum and pathogenesis. Hum. Genomics, 2011; 5: 623-690
  Google Scholar
• 51. Levitt P., Campbell D.B.: The genetic and neurobiologic compasspoints toward common signaling dysfunctions in autism spectrumdisorders. J. Clin. Invest., 2009; 119: 747-754
  Google Scholar
• 52. Li J., McCullough L.D.: Effects of AMP-activated protein kinasein cerebral ischemia. J. Cereb. Blood Flow Metab., 2010; 30: 480-492
  Google Scholar
• 53. Ma L., Chen Z., Erdjument-Bromage H., Tempst P., Pandolfi P.P.: Phosphorylationand functional inactivation of TSC2 by Erk implicationsfor tuberous sclerosis and cancer pathogenesis. Cell, 2005; 121: 179-193
  Google Scholar
• 54. Manning B.D., Cantley L.C.: AKT/PKB signaling: navigating downstream.Cell, 2007; 129: 1261-1274
  Google Scholar
• 55. Muhle R., Trentacoste S.V., Rapin I.: The genetics of autism. Pediatrics,2004; 113: e472-e486
  Google Scholar
• 56. O’Roak B.J., State M.W.: Autism genetics: strategies, challenges,and opportunities. Autism Res., 2008; 1: 4-17
  Google Scholar
• 57. Osborne J.P., Fryer A., Webb D.: Epidemiology of tuberous sclerosis.Ann. N.Y. Acad. Sci., 1991; 615: 125-127
  Google Scholar
• 58. Oshiro N., Yoshino K., Hidayat S., Tokunaga C., Hara K., EguchiS., Avruch J., Yonezawa K.: Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function.Genes Cells, 2004; 9: 359-366
  Google Scholar
• 59. Penagarikano O., Mulle J.G., Warren S.T.: The pathophysiologyof fragile x syndrome. Annu. Rev. Genomics Hum. Genet., 2007; 8:109-129
  Google Scholar
• 60. Perycz M., Świech Ł., Malik A., Jaworski J.: mTOR w fizjologiii patologii układu nerwowego. Postępy Biol. Kom., 2007; 34: 511-525
  Google Scholar
• 61. Reiling J.H., Sabatini D.M.: Stress and mTORture signaling. Oncogene,2006; 25: 6373-6383
  Google Scholar
• 62. Sancak Y., Thoreen C.C., Peterson T.R., Lindquist R.A., Kang S.A.,Spooner E., Carr S.A., Sabatini D.M.: PRAS40 is an insulin-regulatedinhibitor of the mTORC1 protein kinase. Mol. Cell, 2007; 25: 903-915
  Google Scholar
• 63. Sarbassov D.D., Ali S.M., Kim D.H., Guertin D.A., Latek R.R., Erdjument-BromageH., Tempst P., Sabatini D.M.: Rictor, a novel bindingpartner of mTOR, defines a rapamycin-insensitive and raptor–independent pathway that regulates the cytoskeleton. Curr. Biol.,2004; 14: 1296-1302
  Google Scholar
• 64. Sarbassov D.D., Ali S.M., Sengupta S., Sheen J.H., Hsu P.P., BagleyA.F., Markhard A.L., Sabatini D.M.: Prolonged rapamycin treatmentinhibits mTORC2 assembly and Akt/PKB. Mol. Cell, 2006; 22: 159-168
  Google Scholar
• 65. Sarbassov D.D., Guertin D.A., Ali S.M., Sabatini D.M.: Phosphorylationand regulation of Akt/PKB by the rictor-mTOR complex.Science, 2005; 307: 1098-1101
  Google Scholar
• 66. Shahbazian D., Roux P.P., Mieulet V., Cohen M.S., Raught B., TauntonJ., Hershey J.W., Blenis J., Pende M., Sonenberg N.: The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylationand activity. EMBO J., 2006; 25: 2781-2791
  Google Scholar
• 67. Sharma A., Hoeffer C.A., Takayasu Y., Miyawaki T., McBride S.M.,Klann E., Zukin R.S.: Dysregulation of mTOR signaling in fragile Xsyndrome. J. Neurosci., 2010; 30: 694-702
  Google Scholar
• 68. Swiech L., Perycz M., Malik A., Jaworski J.: Role of mTOR in physiologyand pathology of the nervous system. Biochim. Biophys.Acta, 2008; 1784: 116-132
  Google Scholar
• 69. Tavazoie S.F., Alvarez V.A., Ridenour D.A., Kwiatkowski D.J., SabatiniB.L.: Regulation of neuronal morphology and function by thetumor suppressors Tsc1 and Tsc2. Nat. Neurosci., 2005; 8: 1727-1734
  Google Scholar
• 70. Towler M.C., Hardie D.G.: AMP-activated protein kinase in metaboliccontrol and insulin signaling. Circ. Res., 2007; 100: 328-341
  Google Scholar
• 71. Uhlmann E.J., Wong M., Baldwin R.L., Bajenaru M.L., Onda H.,Kwiatkowski D.J., Yamada K., Gutmann D.H.: Astrocyte-specific TSC1conditional knockout mice exhibit abnormal neuronal organizationand seizures. Ann. Neurol., 2002; 52: 285-296
  Google Scholar
• 72. Valentinis B., Baserga R.: IGF-I receptor signalling in transformationand differentiation. Mol. Pathol., 2001; 54: 133-137
  Google Scholar
• 73. Weber A.M., Egelhoff J.C., McKellop J.M., Franz D.N.: Autism andthe cerebellum: evidence from tuberous sclerosis. J. Autism Dev. Disord.,2000; 30: 511-517
  Google Scholar
• 74. WHO. The ICD-10 classification of mental and behavioral disorders:diagnostic criteria for research. Geneva: World Health Organization,1993
  Google Scholar
• 75. Williams C.A., Dagli A., Battaglia A.: Genetic disorders associatedwith macrocephaly. Am. J. Med. Genet. A, 2008; 146A: 2023-2037
  Google Scholar
• 76. Wong M., Ess K.C., Uhlmann E.J., Jansen L.A., Li W., Crino P.B.,Mennerick S., Yamada K.A., Gutmann D.H.: Impaired glial glutamatetransport in a mouse tuberous sclerosis epilepsy model. Ann. Neurol.,2003; 54: 251-256
  Google Scholar
• 77. Wullschleger S., Loewith R., Hall M.N.: TOR signaling in growthand metabolism. Cell, 2006; 124: 471-484
  Google Scholar
• 78. Yakupoglu Y.K., Kahan B.D.: Sirolimus: a current perspective.Exp. Clin. Transplant., 2003; 1: 8-18
  Google Scholar
• 79. Zeng L.H., Xu L.,. Gutmann D.H., Wong M.: Rapamycin preventsepilepsy in a mouse model of tuberous sclerosis complex. Ann. Neurol.,2008; 63: 444-453
  Google Scholar
• 80. Zhou H., Luo Y., Huang S.: Updates of mTOR inhibitors. AnticancerAgents Med. Chem., 2010; 10: 571-581
  Google Scholar
• 81. Zhou J., Blundell J., Ogawa S., Kwon C.H., Zhang W., Sinton C.,Powell C.M., Parada L.F.: Pharmacological inhibition of mTORC1suppresses anatomical, cellular, and behavioral abnormalities inneural-specific Pten knock-out mice. J. Neurosci., 2009; 29: 1773-1783
  Google Scholar

Full text