mTOR, a potential target to treat autism spectrum disorder

CNS and Neurological Disorders - Drug Targets

Volumn 15, Issue 5, 2016, Pages 533-543

  Sato, Atsushi ^a  

^a UNIVERSITY OF TOKYO HOSPITAL   (Japan)

Author keywords

Autophagy; Fragile X syndrome; Mammalian target of rapamycin; Metabotropic glutamate receptor 5; Neurofibromatosis; Phosphatase and tensin homolog; Tuberous sclerosis complex

Indexed keywords

4 AMINOBUTYRIC ACID RECEPTOR BLOCKING AGENT; EVEROLIMUS; FRAGILE X MENTAL RETARDATION PROTEIN; GELATINASE B; INITIATION FACTOR 4F; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; METABOTROPIC RECEPTOR 5; MEVINOLIN; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE; NEUROFIBROMIN; NEURON SPECIFIC ENOLASE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; RAPAMYCIN; RAS PROTEIN; TUBERIN; TUBEROUS SCLEROSIS COMPLEX; UNCLASSIFIED DRUG; WORTMANNIN; TARGET OF RAPAMYCIN KINASE;

ARTICLE; AUTISM; CELL PROLIFERATION; COGNITIVE DEFECT; COMPULSION; COSTELLO SYNDROME; FRAGILE X SYNDROME; GENE DELETION; GENE MUTATION; HUMAN; LONG TERM DEPRESSION; LONG TERM POTENTIATION; MACROCEPHALY; NEUROFIBROMATOSIS TYPE 1; NONHUMAN; NOONAN SYNDROME; PROTEIN PHOSPHORYLATION; RNA TRANSLATION; SIGNAL TRANSDUCTION; SYNAPTIC TRANSMISSION; ANIMAL; ANTAGONISTS AND INHIBITORS; AUTISM SPECTRUM DISORDER; GENETICS; METABOLISM;

ANIMALS; AUTISM SPECTRUM DISORDER; HUMANS; TOR SERINE-THREONINE KINASES;

EID: 84974687454     PISSN: 18715273     EISSN: 19963181     Source Type: Journal    
DOI: 10.2174/1871527315666160413120638     Document Type: Article

References (137)

1. Moschetta M, Reale A, Marasco C, Vacca A, Carratu MR. Therapeutic targeting of the mTOR-signalling pathway in cancer: benefits and limitations. Br J Pharmacol 2014; 171: 3801-13.
2. Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol 2012; 30: 39-68.
3. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149: 274-93.
4. Chong ZZ, Shang YC, Wang S, Maiese K. A Critical Kinase Cascade in Neurological Disorders: PI 3-K, Akt, and mTOR. Future Neurol 2012; 7: 733-48.
5. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing, 2013.
6. Perou R, Bitsko RH, Blumberg SJ, et al. Mental health surveillance among children--United States, 2005-2011. MMWR Surveill Summ 2013; 62: 1-35.
7. Liu X, Takumi T. Genomic and genetic aspects of autism spectrum disorder. Biochem Biophys Res Commun 2014; 452: 244-53.
8. Kim DH, Sarbassov DD, Ali SM, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110: 163-75.
9. Hara K, Maruki Y, Long X, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110: 177-89.
10. Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6: 1122-8.
11. Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptorindependent pathway that regulates the cytoskeleton. Curr Biol 2004; 14: 1296-302.
12. van Slegtenhorst M, Nellist M, Nagelkerken B, et al. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 1998; 7: 1053-7.
13. Plank TL, Yeung RS, Henske EP. Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Res 1998; 58: 4766-70.
14. Wienecke R, Konig A, DeClue JE. Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity. J Biol Chem 1995; 270: 16409-14.
15. Xiao GH, Shoarinejad F, Jin F, Golemis EA, Yeung RS. The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J Biol Chem 1997; 272: 6097-100.
16. Benvenuto G, Li S, Brown SJ, et al. The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination. Oncogene 2000; 19: 6306-16.
17. Ohsawa M, Kobayashi T, Okura H, Igarashi T, Mizuguchi M, Hino O. TSC1 controls distribution of actin fibers through its effect on function of Rho family of small GTPases and regulates cell migration and polarity. PLoS One 2013; 8: e54503.
18. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 2003; 13: 1259-68.
19. Tavares MR, Pavan IC, Amaral CL, Meneguello L, Luchessi AD, Simabuco FM. The S6K protein family in health and disease. Life Sci 2015; 131: 1-10.
20. Poulin F, Gingras AC, Olsen H, Chevalier S, Sonenberg N. 4EBP3, a new member of the eukaryotic initiation factor 4E-binding protein family. J Biol Chem 1998; 273: 14002-7.
21. Sund R, Pukkala E, Pause A, et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function. Nature 1994; 371: 762-7.
22. Gingras AC, Raught B, Gygi SP, et al. Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 2001; 15: 2852-64.
23. Moerke NJ, Aktas H, Chen H, et al. Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 2007; 128: 257-67.
24. Chang YY, Neufeld TP. An Atg1/Atg13 complex with multiple roles in TOR-mediated autophagy regulation. Mol Biol Cell 2009; 20: 2004-14.
25. Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 2009; 284: 12297-305.
26. Northrup H, Krueger DA. International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49: 243-54.
27. National Institutes of Health Consensus Development Conference Statement: neurofibromatosis-Bethesda, MD, USA, July 13-15, 1987. Neurofibromatosis 1988; 1: 172-78.
28. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet 2008; 16: 1289-300.
29. Patja K. Cancer incidence among persons with fragile X syndrome in Finland: a population-based study. J Intellect Disabil Res 2009; 53: 85-90.
30. Bournevell DM. Sclerose tubereuse des circonvolutions cerebrales: idiotie et epilepsie hemiplegique. Arch Neurol 1880; 1: 81-91.
31. van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997; 277: 805-8.
32. European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993; 75: 1305-15.
33. Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008; 372: 657-68.
34. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998; 13: 624-8.
35. Jones AC, Daniells CE, Snell RG, et al. Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum Mol Genet 1997; 6: 2155-61.
36. Dabora SL, Jozwiak S, Franz DN, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001; 68: 64-80.
37. Lewis JC, Thomas HV, Murphy KC, Sampson JR. Genotype and psychological phenotype in tuberous sclerosis. J Med Genet 2004; 41: 203-7.
38. Numis AL, Major P, Montenegro MA, Muzykewicz DA, Pulsifer MB, Thiele EA. Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex. Neurology 2011; 76: 981-7.
39. Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 2010; 51: 1236-41.
40. de Vries PJ, Hunt A, Bolton PF. The psychopathologies of children and adolescents with tuberous sclerosis complex (TSC): a postal survey of UK families. Eur Child Adolesc Psychiatry 2007; 16: 16-24.
41. Krueger DA, Northrup H; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49: 255-65.
42. de Vries PJ, Whittemore VH, Leclezio L, et al. Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist. Pediatr Neurol 2015; 52: 25-35.
43. Richards C, Jones C, Groves L, Moss J, Oliver C. Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis. Lancet Psychiatry 2015; 2(10): 909-16.
44. Caglayan AO. Genetic causes of syndromic and non-syndromic autism. Dev Med Child Neurol 2010; 52: 130-8.
45. Kobayashi T, Minowa O, Sugitani Y, et al. A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice. Proc Natl Acad Sci USA 2001; 98: 8762-7.
46. Kobayashi T, Minowa O, Kuno J, Mitani H, Hino O, Noda T. Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. Cancer Res 1999; 59: 1206-11.
47. Kobayashi T, Hirayama Y, Kobayashi E, Kubo Y, Hino O. A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer. Nat Genet 1995; 9: 70-4.
48. Uhlmann EJ, Wong M, Baldwin RL, et al. Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures. Ann Neurol 2002; 52: 285-96.
49. 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 2009; 18: 1252-65.
50. Tsai PT, Hull C, Chu Y, et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 2012; 488: 647-51.
51. Reith RM, McKenna J, Wu H, et al. Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex. Neurobiol Dis 2013; 51: 93-103.
52. Goorden SM, van Woerden GM, van der Weerd L, Cheadle JP, Elgersma Y. Cognitive deficits in Tsc1+/-mice in the absence of cerebral lesions and seizures. Ann Neurol 2007; 62: 648-55.
53. Sato A, Kasai S, Kobayashi T, et al. Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex. Nat Commun 2012; 3: 1292.
54. Waltereit R, Japs B, Schneider M, de Vries PJ, Bartsch D. Epilepsy and Tsc2 haploinsufficiency lead to autistic-like social deficit behaviors in rats. Behav Genet 2011; 41: 364-72.
55. Ehninger D, Han S, Shilyansky C, et al. Reversal of learning deficits in a Tsc2+/-mouse model of tuberous sclerosis. Nat Med 2008; 14: 843-8.
56. 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 2011; 20: 445-54.
57. 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 2005; 8: 1727-34.
58. Nie D, Di Nardo A, Han JM, et al. Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nat Neurosci 2010; 13: 163-72.
59. Tang G, Gudsnuk K, Kuo SH, et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 2014; 83: 1131-43.
60. Di Nardo A, Wertz MH, Kwiatkowski E, et al. Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1. Hum Mol Genet 2014; 23: 3865-74.
61. Zeng LH, Ouyang Y, Gazit V, et al. Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex. Neurobiol Dis 2007; 28: 184-96.
62. Auerbach BD, Osterweil EK, Bear MF. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 2011; 480: 63-8.
63. Bateup HS, Takasaki KT, Saulnier JL, Denefrio CL, Sabatini BL. Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. J Neurosci 2011; 31: 8862-9.
64. Bateup HS, Johnson CA, Denefrio CL, Saulnier JL, Kornacker K, Sabatini BL. Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron 2013; 78: 510-22.
65. Courchesne E, Karns CM, Davis HR, et al. Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study. Neurology 2001; 57: 245-54.
66. Butler MG, Dasouki MJ, Zhou XP, et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 2005; 42: 318-21.
67. Varga EA, Pastore M, Prior T, Herman GE, McBride KL. The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly. Genet Med 2009; 11: d11-7.
68. McBride KL, Varga EA, Pastore MT, et al. Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly. Autism Res 2010; 3: 137-41.
69. Marsh DJ, Kum JB, Lunetta KL, et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 1999; 8: 1461-72.
70. Zhou XP, Marsh DJ, Morrison CD, et al. Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults. Am J Hum Genet 2003; 73: 1191-8.
71. Sulis ML, Parsons R. PTEN: from pathology to biology. Trends Cell Biol 2003; 13, 478-83.
72. Suzuki A, de la Pompa JL, Stambolic V, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol 1998; 8: 1169-78.
73. Podsypanina K, Ellenson LH, Nemes A, et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci USA 1999; 96: 1563-8.
74. Kwon CH, Luikart BW, Powell CM, et al. Pten regulates neuronal arborization and social interaction in mice. Neuron 2006; 50: 377-88.
75. Zhou J, Blundell J, Ogawa S, et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J Neurosci 2009; 29: 1773-83.
76. Page DT, Kuti OJ, Prestia C, Sur M. Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior. Proc Natl Acad Sci USA 2009; 106: 1989-94.
77. Napoli E, Ross-Inta C, Wong S, et al. Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: interplay between Pten and p53. PLoS One 2012; 7: e42504.
78. Clipperton-Allen AE, Page DT. Pten haploinsufficient mice show broad brain overgrowth but selective impairments in autismrelevant behavioral tests. Hum Mol Genet 2014; 23: 3490-505.
79. Turner G, Webb T, Wake S, Robinson H. Prevalence of fragile X syndrome. Am J Med Genet 1996; 64: 196-7.
80. Kidd SA, Lachiewicz A, Barbouth D, et al. Fragile X syndrome: a review of associated medical problems. Pediatrics 2014; 134: 995-1005.
81. Verkerk AJ, Pieretti M, Sutcliffe JS, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991; 65: 905-14.
82. Naumann A, Hochstein N, Weber S, Fanning E, Doerfler W. A distinct DNA-methylation boundary in the 5'-upstream sequence of the FMR1 promoter binds nuclear proteins and is lost in fragile X syndrome. Am J Hum Genet 2009; 85: 606-16.
83. Brouwer JR, Willemsen R, Oostra BA. The FMR1 gene and fragile X-associated tremor/ataxia syndrome. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 782-98.
84. Bourgeois JA, Seritan AL, Casillas EM, et al. Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers. J Clin Psychiatry 2011; 72: 175-82.
85. Hunter J, Rivero-Arias O, Angelov A, Kim E, Fotheringham I, Leal J. Epidemiology of fragile X syndrome: a systematic review and meta-analysis. Am J Med Genet A 2014; 164A: 1648-58.
86. Darnell JC, Jensen KB, Jin P, Brown V, Warren ST, Darnell RB. Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function. Cell 2001; 107: 489-99.
87. Darnell JC, Mostovetsky O, Darnell RB. FMRP RNA targets: Identification and validation. Genes Brain Behav 2005; 4: 341-49.
88. Sharma A, Hoeffer CA, Takayasu Y, et al. Dysregulation of mTOR signaling in fragile X syndrome. J Neurosci 2010; 30: 694-702.
89. Bakker CE, Verheij C, Willemsen R, et al. Fmr1 knockout mice: a model to study fragile X mental retardation. The Dutch-Belgian Fragile X Consortium. Cell 1994; 78: 23-33.
90. Bernardet M, Crusio WE. Fmr1 KO mice as a possible model of autistic features. ScientificWorldJournal 2006; 6: 1164-76.
91. Kazdoba TM, Leach PT, Silverman JL, Crawley JN. Modeling fragile X syndrome in the Fmr1 knockout mouse. Intractable Rare Dis Res 2014; 3: 118-33.
92. Dahlhaus R, El-Husseini A. Altered neuroligin expression is involved in social deficits in a mouse model of the fragile X syndrome. Behav Brain Res 2010; 208: 96-105.
93. McNaughton CH, Moon J, Strawderman MS, Maclean KN, Evans J, Strupp BJ. Evidence for social anxiety and impaired social cognition in a mouse model of fragile X syndrome. Behav Neurosci 2008; 122: 293-300.
94. Pietropaolo S, Guilleminot A, Martin B, D'Amato FR, Crusio WE. Genetic-background modulation of core and variable autistic-like symptoms in Fmr1 knock-out mice. PLoS One 2011; 6: e17073.
95. Grossman AW, Elisseou NM, McKinney BC, Greenough WT. Hippocampal pyramidal cells in adult Fmr1 knockout mice exhibit an immature-appearing profile of dendritic spines. Brain Res 2006; 1084: 158-64.
96. Rudelli RD, Brown WT, Wisniewski K, et al. Adult fragile X syndrome. Clinico-neuropathologic findings. Acta Neuropathol 1985; 67: 289-95.
97. Huber KM, Gallagher SM, Warren ST, Bear MF. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci USA 2002; 99: 7746-50.
98. Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci 2004; 27: 370-7.
99. Nosyreva ED, Huber KM. Metabotropic receptor-dependent longterm depression persists in the absence of protein synthesis in the mouse model of fragile X syndrome. J Neurophysiol 2006; 95: 3291-5.
100. Seese RR, Babayan AH, Katz AM, et al. LTP induction translocates cortactin at distant synapses in wild-type but not Fmr1 knockout mice. J Neurosci 2012; 32: 7403-13.
101. Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP. Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 2005; 49: 1053-66.
102. Dolen G, Osterweil E, Rao BS, et al. Correction of fragile X syndrome in mice. Neuron 2007; 56: 955-62.
103. Bhakar AL, Dolen G, Bear MF. The pathophysiology of fragile X (and what it teaches us about synapses). Annu Rev Neurosci 2012; 35: 417-43.
104. Lipton JO, Sahin M. The neurology of mTOR. Neuron 2014; 84: 275-91.
105. Hoeffer CA, Sanchez E, Hagerman RJ, et al. Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes Brain Behav 2012; 11: 332-41.
106. Kumari D, Bhattacharya A, Nadel J, et al. Identification of fragile X syndrome specific molecular markers in human fibroblasts: a useful model to test the efficacy of therapeutic drugs. Hum Mutat 2014; 35: 1485-94.
107. Gross C, Nakamoto M, Yao X, et al. Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. J Neurosci 2010; 30: 10624-38.
108. Napoli I, Mercaldo V, Boyl PP, et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 2008; 134: 1042-54.
109. Bhattacharya A, Kaphzan H, Alvarez-Dieppa AC, Murphy JP, Pierre P, Klann E. Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 2012; 76: 325-37.
110. Min WW, Yuskaitis CJ, Yan Q, et al. Elevated glycogen synthase kinase-3 activity in Fragile X mice: key metabolic regulator with evidence for treatment potential. Neuropharmacology 2009; 56: 463-72.
111. Mines MA, Yuskaitis CJ, King MK, Beurel E, Jope RS. GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse model of fragile X syndrome and autism. PLoS One 2010; 5: e9706.
112. Silverman JL, Smith DG, Rizzo SJ, et al. Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Sci Transl Med 2012; 4: 131ra51.
113. Burket JA, Benson AD, Tang AH, Deutsch SI. Rapamycin improves sociability in the BTBR T(+)Itpr3(tf)/J mouse model of autism spectrum disorders. Brain Res Bull 2014; 100: 70-5.
114. Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol 2014; 13: 834-43.
115. Acosta MT, Gioia GA, Silva AJ. Neurofibromatosis type 1: new insights into neurocognitive issues. Curr Neurol Neurosci Rep 2006; 6: 136-43.
116. Walsh KS, Velez JI, Kardel PG, et al. Symptomatology of autism spectrum disorder in a population with neurofibromatosis type 1. Dev Med Child Neurol 2013; 55: 131-8.
117. Garg S, Lehtonen A, Huson SM, et al. Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study. Dev Med Child Neurol 2013; 55: 139-45.
118. Abramowicz A, Gos M. Neurofibromin in neurofibromatosis type 1-mutations in NF1 gene as a cause of disease. Dev Period Med 2014; 18: 297-306.
119. Johannessen CM, Reczek EE, James MF, Brems H, Legius E, Cichowski K. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci USA 2005; 102: 8573-8.
120. Li W, Cui Y, Kushner SA, et al. The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol 2005; 15: 1961-7.
121. Costa RM, Federov NB, Kogan JH, et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 2002; 415: 526-30.
122. Molosh AI, Johnson PL, Spence JP, et al. Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase. Nat Neurosci 2014; 17: 1583-90.
123. Guilding C, McNair K, Stone TW, Morris BJ. Restored plasticity in a mouse model of neurofibromatosis type 1 via inhibition of hyperactive ERK and CREB. Eur J Neurosci 2007; 25: 99-105.
124. Cui Y, Costa RM, Murphy GG, et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 2008; 135: 549-60.
125. Krab LC, de Goede-Bolder A, Aarsen FK, et al. Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. JAMA 2008; 300: 287-94.
126. Pause A, Belsham GJ, Gingras AC, et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function. Nature 1994; 371: 762-7.
127. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18: 1926-45.
128. Koromilas AE, Lazaris-Karatzas A, Sonenberg N. mRNAs containing extensive secondary structure in their 59 non-coding region translate efficiently in cells overexpressing initiation factor eIF-4E. EMBO J 1992; 11: 41538.
129. Neves-Pereira M, Muller B, Massie D, et al. Deregulation of EIF4E: a novel mechanism for autism. J Med Gene 2009; 46: 759-65.
130. Gkogkas CG, Khoutorsky A, Ran I, et al. Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 2013; 493: 371-7.
131. Santini E, Huynh TN, MacAskill AF, et al. Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature 2013; 493: 411-5.
132. Gkogkas CG, Khoutorsky A, Cao R, et al. Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes. Cell Rep 2014; 9: 1742-55.
133. Potter WB, Basu T, O'Riordan KJ, et al. Reduced juvenile longterm depression in tuberous sclerosis complex is mitigated in adults by compensatory recruitment of mGluR5 and Erk signaling. PLoS Biol 2013; 11: e1001627.
134. Davies DM, de Vries PJ, Johnson SR, et al. Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. Clin Cancer Res 2011; 17: 4071-81.
135. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010; 363: 1801-11.
136. Krueger DA, Wilfong AA, Holland-Bouley K, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol 2013; 74: 679-87.
137. Franz DN, Agricola K, Mays M, et al. Everolimus for subependymal giant cell astrocytoma: 5-year final analysis. Ann Neurol 2015; 78(6): 929-38.