Review

mTOR signaling in proteostasis and its relevance to autism spectrum disorders

  • Received: 24 October 2016 Accepted: 12 January 2017 Published: 19 January 2017
  • Proteins are extremely labile cellular components, especially at physiological temperatures. The appropriate regulation of protein levels, or proteostasis, is essential for all cells. In the case of highly polarized cells like neurons, proteostasis is also crucial at synapses, where quick confined changes in protein composition occur to support synaptic activity and plasticity. The accurate regulation of those cellular processes controlling protein synthesis and degradation is necessary for proteostasis, and its deregulation has deleterious consequences in brain function. Alterations in those cellular mechanisms supporting synaptic protein homeostasis have been pinpointed in autism spectrum disorders such as tuberous sclerosis, neurofibromatosis 1, PTEN-related disorders, fragile X syndrome, MECP2 disorders and Angelman syndrome. Proteostasis alterations in these disorders share the alterations in mechanistic/mammalian target of rapamycin (mTOR) signaling pathway, an intracellular pathway with key synaptic roles. The aim of the present review is to describe the recent literature on the major cellular mechanisms involved in proteostasis regulation in the synaptic context, and its association with mTOR signaling deregulations in various autism spectrum disorders. Altogether, the cellular and molecular mechanisms in synaptic proteostasis could be the foundation for novel shared therapeutic strategies that would take advantage of targeting common disorder mechanisms.

    Citation: Judit Faus-Garriga, Isabel Novoa, Andrés Ozaita. mTOR signaling in proteostasis and its relevance to autism spectrum disorders[J]. AIMS Biophysics, 2017, 4(1): 63-89. doi: 10.3934/biophy.2017.1.63

    Related Papers:

  • Proteins are extremely labile cellular components, especially at physiological temperatures. The appropriate regulation of protein levels, or proteostasis, is essential for all cells. In the case of highly polarized cells like neurons, proteostasis is also crucial at synapses, where quick confined changes in protein composition occur to support synaptic activity and plasticity. The accurate regulation of those cellular processes controlling protein synthesis and degradation is necessary for proteostasis, and its deregulation has deleterious consequences in brain function. Alterations in those cellular mechanisms supporting synaptic protein homeostasis have been pinpointed in autism spectrum disorders such as tuberous sclerosis, neurofibromatosis 1, PTEN-related disorders, fragile X syndrome, MECP2 disorders and Angelman syndrome. Proteostasis alterations in these disorders share the alterations in mechanistic/mammalian target of rapamycin (mTOR) signaling pathway, an intracellular pathway with key synaptic roles. The aim of the present review is to describe the recent literature on the major cellular mechanisms involved in proteostasis regulation in the synaptic context, and its association with mTOR signaling deregulations in various autism spectrum disorders. Altogether, the cellular and molecular mechanisms in synaptic proteostasis could be the foundation for novel shared therapeutic strategies that would take advantage of targeting common disorder mechanisms.


    加载中
    [1] Gumeni S, Trougakos IP (2016) Cross talk of proteostasis and mitostasis in cellular homeodynamics, ageing, and disease. Oxidative Medicine and Cellular Longevity 2016: 4587691.
    [2] Ruegsegger C, Saxena S (2016) Proteostasis impairment in ALS. Brain Res S0006-8993: 30161–30165.
    [3] Pluquet O, Pourtier A, Abbadie C (2015) The unfolded protein response and cellular senescence. A review in the theme: cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. Am J Physiol Cell Physiol 308: C415–C425.
    [4] Klein ME, Monday H, Jordan BA (2016) Proteostasis and RNA binding proteins in synaptic plasticity and in the pathogenesis of neuropsychiatric disorders. Neural Plast 2016: 3857934.
    [5] Nakada C, Ritchie K, Oba Y, et al. (2003) Accumulation of anchored proteins forms membrane diffusion barriers during neuronal polarization. Nat Cell Biol 5: 626–632. doi: 10.1038/ncb1009
    [6] Guillery RW (2005) Observations of synaptic structures: origins of the neuron doctrine and its current status. Philos Trans R Soc Lond B Biol Sci 360: 1281–1307. doi: 10.1098/rstb.2003.1459
    [7] Citri A, Malenka RC (2008) Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology 33: 18–41. doi: 10.1038/sj.npp.1301559
    [8] Kessels HW, Malinow R (2009) Synaptic AMPA receptor plasticity and behavior. Neuron 61: 340–350. doi: 10.1016/j.neuron.2009.01.015
    [9] Hardingham N, Dachtler J, Fox K (2013) The role of nitric oxide in pre-synaptic plasticity and homeostasis. Front Cell Neurosci 7: 190.
    [10] Hashimotodani Y, Ohno-Shosaku T, Kano M (2007) Endocannabinoids and synaptic function in the CNS. Neuroscientist 13: 127–137. doi: 10.1177/1073858406296716
    [11] Casadio A, Martin KC, Giustetto M, et al. (1999) A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell 99: 221–237. doi: 10.1016/S0092-8674(00)81653-0
    [12] Huber KM,Kayser MS, Bear MF (2000) Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288: 1254–1256.
    [13] Bradshaw KD, Emptage NJ, Bliss TV (2003) A role for dendritic protein synthesis in hippocampal late LTP. Eur J Neurosci 18: 3150–3152.
    [14] Yin HH, Davis MI, Ronesi JA, et al. (2006) The role of protein synthesis in striatal long-term depression. J Neurosci 26: 11811–11820. doi: 10.1523/JNEUROSCI.3196-06.2006
    [15] Zhang Y, Nicholatos J, Dreier JR, et al. (2014) Coordinated regulation of protein synthesis and degradation by mTORC1. Nature 513: 440–443. doi: 10.1038/nature13492
    [16] Louros SR, Osterweil EK (2016) Perturbed proteostasis in autism spectrum disorders. J Neurochem 139: 1081–1092. doi: 10.1111/jnc.13723
    [17] American Psychiatric Association, (2013) Diagnostic and Statistical Manual of Mental Disorders: DSM-5, Arlington, Virginia: USA American Psychiatric Association.
    [18] de la Torre-Ubieta L, Won H, Stein JL, et al. (2016) Advancing the understanding of autism disease mechanisms through genetics. Nat Med 22: 345–361.
    [19] Geschwind DH, State MW (2015) Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol 14: 1109–1120.
    [20] Jaworski J, Sheng M (2006) The growing role of mTOR in neuronal development and plasticity. Mol Neurobiol 34: 205–219. doi: 10.1385/MN:34:3:205
    [21] Bockaert J, Marin P (2015) mTOR in brain physiology and pathologies. Physiol Rev 95: 1157–1187. doi: 10.1152/physrev.00038.2014
    [22] Bramham CR, Wells DG (2007) Dendritic mRNA: transport, translation and function. Nat Rev Neurosci 8: 776–789.
    [23] Wang DO, Kim SM, Zhao Y, et al. (2009) Synapse- and stimulus-specific local translation during long-term neuronal plasticity. Science 324: 1536–1540. doi: 10.1126/science.1173205
    [24] Andreassi C, Riccio A (2009)To localize or not to localize: mRNA fate is in 3'UTRends. Trends Cell Biol 19: 465–474.
    [25] Besse F, Ephrussi A (2008) Translational control of localized mRNAs: restricting protein synthesis in space and time. Nat Rev Mol Cell Biol 9: 971–980.
    [26] Redondo RL, Morris R (2011) Making memories last: the synaptic tagging and capture hypothesis. Nat Rev Neurosci 12: 17–30. doi: 10.1038/nrn2963
    [27] Richter JD, Klann E (2009) Making synaptic plasticity and memory last: mechanisms of translational regulation. Genes Dev 23: 1–11. doi: 10.1101/gad.1735809
    [28] Thomas MG, Pascual ML, Maschi D, et al. (2014) Synaptic control of local translation: the plot thickens with new characters. Cell Mol Life Sci 71: 2219–2239. doi: 10.1007/s00018-013-1506-y
    [29] Doyle M, Kiebler MA (2011) Mechanisms of dendritic mRNA transport and its role in synaptic tagging. EMBO J 30: 3540–3552. doi: 10.1038/emboj.2011.278
    [30] Mayford M, Baranes D, Podsypanina K, et al. (1996) The 3'-untranslated region of CaMKII alpha is a cis-acting signal for the localization and translation of mRNA in dendrites. Proc Natl Acad Sci USA 93: 13250–13255. doi: 10.1073/pnas.93.23.13250
    [31] Kislauskis EH, Li Z, Singer RH, et al. (1993) Isoform-specific 3'-untranslated sequences sort alpha-cardiac and beta-cytoplasmic actin messenger RNAs to different cytoplasmic compartments. J Cell Biol 123: 165–172. doi: 10.1083/jcb.123.1.165
    [32] Blichenberg A, Schwanke B, Rehbein M, et al. (1999) Identification of a cis-acting dendritic targeting element in MAP2 mRNAs. J Neurosci 19: 8818–8829.
    [33] Kobayashi H, Yamamoto S, Maruo T, et al. (2005) Identification of a cis-acting element required for dendritic targeting of activity-regulated cytoskeleton-associated protein mRNA. Eur J Neurosci 22: 2977–2984. doi: 10.1111/j.1460-9568.2005.04508.x
    [34] An JJ, Gharami K, Liao GY, et al. (2008) Distinct role of long 3' UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134: 175–187. doi: 10.1016/j.cell.2008.05.045
    [35] Glanzer J, Miyashiro KY, Sul JY, et al. (2005) RNA splicing capability of live neuronal dendrites. Proc Natl Acad Sci USA 102: 16859–16864. doi: 10.1073/pnas.0503783102
    [36] Chawla G, Lin CH, Han A, et al. (2009) Sam68 regulates a set of alternatively spliced exons during neurogenesis. Mol Cell Biol 29: 201–213. doi: 10.1128/MCB.01349-08
    [37] Matter N, Herrlich P, König H (2002) Signal-dependent regulation of splicing via phosphorylation of Sam68. Nature 420: 691–695. doi: 10.1038/nature01153
    [38] Khaladkar M, Buckley PT, Lee MT, et al. (2013) Subcellular RNA sequencing reveals broad presence of cytoplasmic intron-sequence retaining transcripts in mouse and rat neurons. PLoS One 8: 1–13.
    [39] Buckley PT, Lee MT, Sul JY, et al. (2011) Cytoplasmic intron sequence-retaining transcripts can be dendritically targeted via ID element retrotransposons. Neuron 69: 877–884.
    [40] Buchan JR (2014) mRNP granules. Assembly, function, and connections with disease. RNA Biol 11: 1019–1030.
    [41] Fritzsche R, Karra D, Bennett KL, et al. (2013) Interactome of two diverse RNA granules links mRNA localization to translational repression in neurons. Cell Rep 5: 1749–1762.
    [42] Ivanov PA, Chudinova EM, Nadezhdina ES (2003) Disruption of microtubules inhibits cytoplasmic ribonucleoprotein stress granule formation. Exp Cell Res 290: 227–233. doi: 10.1016/S0014-4827(03)00290-8
    [43] Hirokawa N (2006) mRNA transport in dendrites: RNA granules, motors, and tracks. J Neurosci 26: 7139–7142. doi: 10.1523/JNEUROSCI.1821-06.2006
    [44] Martin KC, Ephrussi A (2009) mRNA localization: gene expression in the spatial dimension. Cell 136: 719–730. doi: 10.1016/j.cell.2009.01.044
    [45] Kapeli K, Yeo GW (2012) Genome-wide approaches to dissect the roles of RNA binding proteins in translational control: implications for neurological diseases. Front Neurosci 6: 144.
    [46] Laggerbauer B, Ostareck D, Keidel EM, et al. (2001) Evidence that fragile X mental retardation protein is a negative regulator of translation. Hum Mol Genet 10: 329–338. doi: 10.1093/hmg/10.4.329
    [47] Hüttelmaier S, Zenklusen D, Lederer M, et al. (2005) Spatial regulation of β-actin translation by Src-dependent phosphorylation of ZBP1. Nature 438: 512–515.
    [48] Darnell JC, Richter JD (2012) Cytoplasmic RNA-binding proteins and the control of complex brain function. Cold Spring Harb Perspect Biol 4: a012344.
    [49] Klein ME, Younts TJ, Castillo PE, et al. (2013) RNA-binding protein Sam68 controls synapse number and local β-actin mRNA metabolism in dendrites. Proc Natl Acad Sci USA 110: 3125–3130. doi: 10.1073/pnas.1209811110
    [50] Grange J, Belly A, Dupas S, et al. (2009) Specific interaction between Sam68 and neuronal mRNAs: implication for the activity-dependent biosynthesis of elongation factor eEF1A. J Neurosci Res 87: 12–25.
    [51] Eom T, Antar LN, Singer RH, et al. (2003) Localization of a beta-actin messenger ribonucleoprotein complex with zipcode-binding protein modulates the density of dendritic filopodia and filopodial synapses. J Neurosci 23: 10433–10444.
    [52] Itoh M, Haga I, Li QH, et al. (2002) Identification of cellular mRNA targets for RNA-binding protein Sam68. Nucleic Acids Res 30: 5452–5464. doi: 10.1093/nar/gkf673
    [53] Jung MY, Lorenz L, Richter JD (2006) Translational control by neuroguidin, a eukaryotic initiation factor 4E and CPEB binding protein. Mol Cell Biol 26: 4277–4287. doi: 10.1128/MCB.02470-05
    [54] Richter JD, Sonenberg N (2005) Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433: 477–480. doi: 10.1038/nature03205
    [55] Ivshina M, Lasko P, Richter JD (2014) Cytoplasmic polyadenylation element binding proteins in development, health, and disease. Annu Rev Cell Dev Biol 30: 393–415. doi: 10.1146/annurev-cellbio-101011-155831
    [56] Huang YS, Jung MY, Sarkissian M, et al. (2002) N-methyl-D-aspartate receptor signaling results in Aurora kinase-catalyzed CPEB phosphorylation and alpha CaMKII mRNA polyadenylation at synapses. EMBO J 21: 2139–2148. doi: 10.1093/emboj/21.9.2139
    [57] Wang CF, Huang YS (2012) Calpain 2 activated through N-methyl-D-aspartic acid receptor signaling cleaves CPEB3 and abrogates CPEB3-repressed translation in neurons. Mol Cell Biol 32: 3321–3332. doi: 10.1128/MCB.00296-12
    [58] Siomi H, Siomi MC, Nussbaum RL, et al. (1993) The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein. Cell 74: 291–298. doi: 10.1016/0092-8674(93)90420-U
    [59] Verkerk AJ, Pieretti M, Sutcliffe JS, et al. (1991) Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65: 905–914. doi: 10.1016/0092-8674(91)90397-H
    [60] Tsuboi D, Kuroda K, Tanaka M, et al. (2015) Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity. Nat Neurosc 18: 698–707.
    [61] Cohen TJ, Lee VM, Trojanowski JQ (2011) TDP-43 functions and pathogenic mechanisms implicated in TDP-43 proteinopathies. Trends Mol Med 17: 659–667.
    [62] Koyama A, Sugai A, Kato T, et al. (2016) Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43. Nucleic Acids Res 44: 5820–5836. doi: 10.1093/nar/gkw499
    [63] Udagawa T, Farny NG, Jakovcevski M, et al. (2013) Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nat Med 19: 1473–1477. doi: 10.1038/nm.3353
    [64] Iacoangeli A, Tiedge H (2013) Translational control at the synapse: role of RNA regulators. Trends Biochem Sci 38: 47–55. doi: 10.1016/j.tibs.2012.11.001
    [65] Santini E, Huynh TN, Klann E (2014) Mechanisms of translation control underlying long-lasting synaptic plasticity and the consolidation of long-term memory. Prog Mol Biol Transl Sci 122: 131–167. doi: 10.1016/B978-0-12-420170-5.00005-2
    [66] Sonenberg N, Hinnebusch AG (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136: 731–745. doi: 10.1016/j.cell.2009.01.042
    [67] Thoreen CC (2013) Many roads from mTOR to eIF4F. Biochem Soc Trans 41: 913–916. doi: 10.1042/BST20130082
    [68] Pyronnet S (2000) Phosphorylation of the capbinding protein eIF4E by the MAPK-activated protein kinase Mnk1. Biochem Pharmacol 60: 1237–1243. doi: 10.1016/S0006-2952(00)00429-9
    [69] Panja D, Dagyte G, Bidinosti M, et al. (2009) Novel translational control in Arc-dependent long term potentiation consolidation in vivo. J Biol Chem 284: 31498–31511. doi: 10.1074/jbc.M109.056077
    [70] Tang SJ, Reis G, Kang H, et al. (2002) A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc Natl Acad Sci USA 99: 467–472. doi: 10.1073/pnas.012605299
    [71] Vilchez D, Saez I, Dillin A (2014) The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat Commun 5: 5659. doi: 10.1038/ncomms6659
    [72] Yi JJ, Ehlers MD (2005) Ubiquitin and protein turnover in synapse function. Neuron 47: 629–632. doi: 10.1016/j.neuron.2005.07.008
    [73] Hamilton AM, Zito K (2013) Breaking it down: the ubiquitin proteasome system in neuronal morphogenesis. Neural Plast 2013: 196848.
    [74] Bingol B, Schuman EM (2005) Synaptic protein degradation by the ubiquitin proteasome system. Curr Opin Neurobiol 15: 536–541.
    [75] Ravid T, Hochstrasser M (2008) Diversity of degradation signals in the ubiquitin-proteasome system. Nat Rev Mol Cell Biol 9: 679–690. doi: 10.1038/nrm2468
    [76] Hegde AN (2010) The ubiquitin-proteasome pathway and synaptic plasticity. Learn Mem 17: 314–327. doi: 10.1101/lm.1504010
    [77] Bingol B, Sheng M (2011) Deconstruction for reconstruction: the role of proteolysis in neural plasticity and disease. Neuron 69: 22–32. doi: 10.1016/j.neuron.2010.11.006
    [78] Bingol B, Schuman EM (2006) Activity-dependent dynamics and sequestration of proteasomes in dendritic spines. Nature 441: 1144–1148. doi: 10.1038/nature04769
    [79] Hegde AN (2016) Proteolysis, synaptic plasticity and memory. Neurobiol Learn Mem S1074-7427: 30178–30172.
    [80] Li Q, Korte M, Sajikumar S (2016) Ubiquitin-proteasome system inhibition promotes long-term depression and synaptic tagging/capture. Cereb Cortex 26: 2541–2548. doi: 10.1093/cercor/bhv084
    [81] Ciechanover A, Kwon YT (2015) Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. ExpMol Med 47: e147.
    [82] Tarpey PS, Raymond FL, O'Meara S, et al. (2007) Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pescavus, and tremor. Am J Hum Genet 80: 345–352. doi: 10.1086/511134
    [83] Dong C, Bach SV, Haynes KA, et al. (2014) Proteasome modulates positive and negative translational regulators in long-term synaptic plasticity. J Neurosci 34: 3171–3182. doi: 10.1523/JNEUROSCI.3291-13.2014
    [84] Johnson CW, Melia TJ, Yamamoto A (2012) Modulating macroautophagy: a neuronal perspective. Future Med Chem 4: 1715–1731. doi: 10.4155/fmc.12.112
    [85] Komatsu M, Waguri S, Chiba T, et al. (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006 441: 880–884.
    [86] Mizushima N, Komatsu M (2011) Autophagy: renovation of cells and tissues. Cell 147: 728–741. doi: 10.1016/j.cell.2011.10.026
    [87] Hu Z, Yang B, Mo X, et al. (2015) Mechanism and regulation of autophagy and its role in neuronal diseases. Mol Neurobiol 52: 1190–1209. doi: 10.1007/s12035-014-8921-4
    [88] Tang G, Gudsnuk K, Kuo SH, et al. (2014) Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83: 1131–1143. doi: 10.1016/j.neuron.2014.07.040
    [89] Penzes P, Cahill ME, Jones KA, et al. (2011) Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 14: 285–293. doi: 10.1038/nn.2741
    [90] Riccomagno MM, Kolodkin AL (2015) Sculpting neural circuits by axon and dendrite pruning. Annu Rev Cell Dev Biol 31: 779–805. doi: 10.1146/annurev-cellbio-100913-013038
    [91] Jung CH, Ro SH, Cao J, et al. (2010) mTOR regulation of autophagy. FEBS Lett 584: 1287–1295. doi: 10.1016/j.febslet.2010.01.017
    [92] Lipton JO, Sahin M (2014) The neurology of mTOR. Neuron 84: 275–291. doi: 10.1016/j.neuron.2014.09.034
    [93] Roohi A, Hojjat-Farsangi M (2016) Recent Advances in targeting mTORsignaling pathway using small molecule inhibitors. J Drug Target 15: 1–37.
    [94] Jacinto E, Loewith R, Schmidt A, et al. (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6: 1122–1128. doi: 10.1038/ncb1183
    [95] Gaubitz C, Prouteau M, Kusmider B, et al. (2016) TORC2 structure and function. Trends Biochem Sci 41: 532–545. doi: 10.1016/j.tibs.2016.04.001
    [96] Huang W, Zhu PJ, Zhang S, et al. (2013) mTORC2 controls actin polymerization required for consolidation of long-term memory. Nat Neurosci 16: 441–448. doi: 10.1038/nn.3351
    [97] Johnson JL, Huang W, Roman G, et al. (2015) TORC2: a novel target for treating age-associated memory impairment. Sci Rep 5: 15193. doi: 10.1038/srep15193
    [98] Lenz G, Avruch J (2005) Glutamatergic regulation of the p70S6 kinase in primary mouse neurons. J Biol Chem 280: 38121–38124. doi: 10.1074/jbc.C500363200
    [99] Takei N, Inamura N, Kawamura M, et al. (2004) Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci 24: 9760–9769. doi: 10.1523/JNEUROSCI.1427-04.2004
    [100] Lee CC, Huang CC, Wu MY, et al. (2005) Insulin stimulates postsynaptic density-95 protein translation via the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway. J Biol Chem 280: 18543–18550. doi: 10.1074/jbc.M414112200
    [101] Costa-Mattioli M, Monteggia LM (2013) mTOR complexes in neurodevelopmental and neuropsychiatric disorders. Nat Neurosci 16: 1537–1543. doi: 10.1038/nn.3546
    [102] Sosanya NM, Cacheaux LP, Workman ER, et al. (2015) Mammalian target of rapamycin (mTOR) tagging promotes dendritic branch variability through the capture of Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) mRNAs by the RNA-binding protein HuD. J Biol Chem 290: 16357–16371. doi: 10.1074/jbc.M114.599399
    [103] Meyuhas O, Kahan T (2015) The race to decipher the top secrets of TOP mRNAs. Biochim Biophys Acta 1849: 801–811. doi: 10.1016/j.bbagrm.2014.08.015
    [104] Ehninger D, Han S, Shilyansky C, et al. (2008) Reversal of learning deficits in a Tsc2+/– mouse model of tuberous sclerosis. Nat Med 14: 843–848.
    [105] Kwon CH, Luikart BW, Powell CM, et al. (2006) Pten regulates neuronal arborization and social interaction in mice. Neuron 50: 377–388. doi: 10.1016/j.neuron.2006.03.023
    [106] Hoeffer CA, Sanchez E, Hagerman RJ, et al. (2012) Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes Brain Behav 11: 332–341. doi: 10.1111/j.1601-183X.2012.00768.x
    [107] Sharma A, Hoeffer CA, Takayasu Y, et al. (2010) Deregulation of mTOR signaling in fragile X syndrome. J Neurosci 30: 694–702.
    [108] Ricciardi S, Boggio EM, Grosso S, et al. (2011) Reduced AKT/mTOR signaling and protein synthesis deregulation in a Rett syndrome animal model. Hum Mol Genet 20: 1182–1196. doi: 10.1093/hmg/ddq563
    [109] Ramocki MB, Tavyev YJ, Peters SU (2010) The MECP2 duplication syndrome. Am J Med Genet A 152A: 1079–1088. doi: 10.1002/ajmg.a.33184
    [110] Sun J, Liu Y, Moreno S, et al. (2015) Imbalanced mechanistic target of rapamycin C1 and C2 activity in the cerebellum of Angelman syndrome mice impairs motor function. J Neurosci 35: 4706–4718. doi: 10.1523/JNEUROSCI.4276-14.2015
    [111] Stornetta RL, Zhu JJ (2011) Ras and Rap signaling in synaptic plasticity and mental disorders. Neuroscientist 17: 54–78. doi: 10.1177/1073858410365562
    [112] Phillips M, Pozzo-Miller L (2015) Dendritic spine dysgenesis in autism related disorders. Neurosci Lett 601: 30–40. doi: 10.1016/j.neulet.2015.01.011
    [113] Huber KM, Klann E, Costa-Mattioli M, et al. (2015) Deregulation of mammalian target of rapamycin signaling in mouse models of autism. J Neurosci 35: 13836–13842.
    [114] Kelleher RJ III, Bear MF (2008) The autistic neuron: troubled translation? Cell 135: 401–406. doi: 10.1016/j.cell.2008.10.017
    [115] Zhou J, Blundell J, Ogawa S, et al. (2009) Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J Neurosci 29: 1773–1783. doi: 10.1523/JNEUROSCI.5685-08.2009
    [116] Busquets-Garcia A, Gomis-González M, Guegan T, et al. (2013) Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat Med 19: 603–607. doi: 10.1038/nm.3127
    [117] Sun J, Liu Y, Tran J, et al. (2016) mTORC1-S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice. Cell Mol Life Sci 73: 4303–4314. doi: 10.1007/s00018-016-2269-z
    [118] van Slegtenhorst M, de Hoogt R, Hermans C, et al. (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277: 805–808. doi: 10.1126/science.277.5327.805
    [119] European Chromosome 16 Tuberous Sclerosis Consortium (1993) Identification andcharacterization of the tuberous sclerosis gene on chromosome 16. Cell 75: 1305–1315.
    [120] Kwiatkowski DJ, Manning BD (2005) Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum Mol Genet 14 Spec No. 2: R251–R258.
    [121] Hwang SK, Lee JH, Yang JE, et al. (2016) Everolimus improves neuropsychiatric symptoms in a patient with tuberous sclerosis carrying a novel TSC2 mutation. Mol Brain 9: 56. doi: 10.1186/s13041-016-0222-6
    [122] Meikle L, Pollizzi K, Egnor A, et al. (2008) Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci 28: 5422–5432. doi: 10.1523/JNEUROSCI.0955-08.2008
    [123] Sato A, Kasai S, Kobayashi T, et al. (2012) Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex. Nat Commun 3: 1292.
    [124] Williams VC, Lucas J, Babcock MA, et al., (2009) Neurofibromatosis type 1 revisited. Pediatrics 123: 124–133. doi: 10.1542/peds.2007-3204
    [125] Garg S, Plasschaert E, Descheemaeker MJ, et al. (2015) Autism spectrum disorder profile in neurofibromatosis type I. J Autism Dev Disord 45: 1649–1657.
    [126] Plasschaert E, Descheemaeker MJ, Van Eylen L, et al. (2015) Prevalence of autism spectrum disorder symptoms in children with neurofibromatosis type 1. Am J Med Genet B Neuropsychiatr Genet 168B: 72–80.
    [127] Basu TN, Gutmann DH, Fletcher JA, et al. (1992) Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 356: 713–715.
    [128] Guilding C, McNair K, Stone TW, et al. (2007) Restored plasticity in a mouse model of neurofibromatosis type 1 via inhibition of hyperactive ERK and CREB. Eur J Neurosci 25: 99–105. doi: 10.1111/j.1460-9568.2006.05238.x
    [129] Wang Y, Kim E, Wang X, et al. (2012) ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities. Cell 150: 816–830. doi: 10.1016/j.cell.2012.06.034
    [130] Acosta MT, Kardel PG, Walsh KS, et al. (2011) Lovastatin as treatment for neurocognitive deficits in neurofibromatosis type 1: phase I study. PediatrNeurol 45: 241–245.
    [131] Li W, Cui Y, Kushner SA, et al. (2005) The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol 15: 1961–1967. doi: 10.1016/j.cub.2005.09.043
    [132] Osterweil EK, Chuang SC, Chubykin AA, et al. (2013) Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron 77: 243–250. doi: 10.1016/j.neuron.2012.01.034
    [133] Waite KA, Eng C (2002) Protean PTEN: form and function. Am J Hum Genet 70: 829–844.
    [134] Butler MG, Dasouki MJ, Zhou XP, et al. (2005) Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 42: 318–321. doi: 10.1136/jmg.2004.024646
    [135] Goffin A, Hoefsloot LH, Bosgoed E, et al. (2001) PTEN mutation in a family with Cowden syndrome and autism. Am J Med Genet 105: 521–524. doi: 10.1002/ajmg.1477
    [136] Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273: 13375–13378.
    [137] Penagarikano O, Mulle JG, Warren ST (2007) The pathophysiology of fragile X syndrome. Annu Rev Genomics Hum Genet 8: 109–129. doi: 10.1146/annurev.genom.8.080706.092249
    [138] Brown V, Jin P, Ceman S, et al. (2001) Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell 107: 477–487.
    [139] Darnell JC, Van Driesche SJ, Zhang C, et al. (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146: 247–261.
    [140] Gross C, Nakamoto M, Yao X, et al. (2010) Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. J Neurosci 30: 10624–10638. doi: 10.1523/JNEUROSCI.0402-10.2010
    [141] Gross C, Chang CW, Kelly SM, et al (2015) Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. Cell Rep 11: 727–736. doi: 10.1016/j.celrep.2015.03.060
    [142] Darnell JC, Klann E (2013) The translation of translational control by FMRP: therapeutic targets for FXS. Nat Neurosci 16: 1530–1536.
    [143] Richter JD, Bassell GJ, Klann E (2015) Deregulation and restoration of translational homeostasis in fragile X syndrome. Nat Rev Neurosci 16: 595–605. doi: 10.1038/nrn4001
    [144] Osterweil EK, Krueger DD, Reinhold K, et al. (2010) Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome. J Neurosci 30: 15616–15627. doi: 10.1523/JNEUROSCI.3888-10.2010
    [145] Tsai NP, Wilkerson JR, Guo W, et al. (2012) Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95. Cell 151: 1581–1594. doi: 10.1016/j.cell.2012.11.040
    [146] Busquets-Garcia A, Maldonado R, Ozaita A (2014) New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model. Int J Biochem Cell Biol 53: 121–126. doi: 10.1016/j.biocel.2014.05.004
    [147] Berry-Kravis E, Des Portes V, Hagerman R, et al. (2016) Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials. Sci Transl Med 8: 321ra5.
    [148] Shepherd GM, Katz DM (2011) Synaptic microcircuit dysfunction in genetic models of neurodevelopmental disorders: focus on Mecp2 and Met. Curr Opin Neurobiol 21: 827–833. doi: 10.1016/j.conb.2011.06.006
    [149] Lombardi LM, Baker SA, Zoghbi HY (2015) MECP2 disorders: from the clinic to mice and back. J Clin Invest 125: 2914–2923. doi: 10.1172/JCI78167
    [150] Chahrour M, Jung SY, Shaw C, et al. (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320: 1224–1229. doi: 10.1126/science.1153252
    [151] Jiang M, Ash RT, Baker SA, et al. (2013) Dendritic arborization and spine dynamics are abnormal in the mouse model of MECP2 duplication syndrome. J Neurosci 33: 19518–19533. doi: 10.1523/JNEUROSCI.1745-13.2013
    [152] Buiting K, Williams C, Horsthemke B (2016) Angelman syndrome-insights into a rare neurogenetic disorder. Nat Rev Neurol 12: 584–593. doi: 10.1038/nrneurol.2016.133
    [153] Kishino T, Lalande M, Wagstaff J (1997) UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 15: 70–73. doi: 10.1038/ng0197-70
    [154] Vu TH, Hoffman AR (1997) Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. Nat Genet 17: 12–13. doi: 10.1038/ng0997-12
    [155] Reiter LT, Seagroves TN, Bowers M, et al. (2006) Expression of the Rho-GEF Pbl/ECT2 is regulated by the UBE3A E3 ubiquitin ligase. Hum Mol Genet 15: 2825–2835. doi: 10.1093/hmg/ddl225
    [156] Jiang YH, Armstrong D, Albrecht U, et al. (1998) Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21: 799–811. doi: 10.1016/S0896-6273(00)80596-6
    [157] Mishra A, Godavarthi SK, Jana NR (2009) UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27. Neurobiol Dis 36: 26–34. doi: 10.1016/j.nbd.2009.06.010
    [158] Kumar S, Talis AL, Howley PM (1999) Identification of HHR23A as a substrate for E6-associated protein-mediated ubiquitination. J Biol Chem 274: 18785–18792. doi: 10.1074/jbc.274.26.18785
    [159] Greer PL, Hanayama R, Bloodgood BL, et al. (2010) The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 140: 704–716. doi: 10.1016/j.cell.2010.01.026
    [160] Margolis SS, Salogiannis J, Lipton DM, et al. (2010) EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell 143: 442–455. doi: 10.1016/j.cell.2010.09.038
    [161] Jay V, Becker LE, Chan FW, et al. (1991) Puppet-like syndrome of Angelman: a pathologic and neurochemical study. Neurology 41: 416–422. doi: 10.1212/WNL.41.3.416
    [162] Hethorn WR, Ciarlone SL, Filonova I, et al. (2015) Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome. Eur J Neurosci 41: 1372–1380. doi: 10.1111/ejn.12893
    [163] Krishnan A, Zhang R, Yao V, et al. (2016) Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder. Nat Neurosci 19: 1454–1462. doi: 10.1038/nn.4353
    [164] Kilpinen H, Ylisaukko-Oja T, Hennah W, et al. (2008) Association of DISC1 with autism and Asperger syndrome. Mol Psychiatry 13: 187–196. doi: 10.1038/sj.mp.4002031
    [165] Thomson PA, Parla JS, McRae AF, et al. (2014) 708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits. Mol Psychiatry 19: 668–675. doi: 10.1038/mp.2013.68
    [166] Iossifov I, O'Roak BJ, Sanders SJ, et al. (2014) The contribution of de novo coding mutations to autism spectrum disorder. Nature 515: 216–221. doi: 10.1038/nature13908
    [167] Krumm N, Turner TN, Baker C, et al. (2015) Excess of rare, inherited truncating mutations in autism. Nat Genet 47: 582–588. doi: 10.1038/ng.3303
    [168] Brett M, McPherson J, Zang ZJ, et al. (2014) Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel. PLoS One 9: e93409. doi: 10.1371/journal.pone.0093409
    [169] Grønskov K, Brøndum-Nielsen K, Dedic A, et al. (2011) A nonsense mutation in FMR1 causing fragile X syndrome. Eur J Hum Genet 19: 489–491. doi: 10.1038/ejhg.2010.223
    [170] Vincent JB, Konecki DS, Munstermann E, et al. (1996) Point mutation analysis of the FMR1 gene in autism. Mol Psychiatry 1: 227–231.
    [171] Girirajan S, Dennis MY, Baker C, et al. (2013) Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am J Hum Genet 92: 221–237. doi: 10.1016/j.ajhg.2012.12.016
    [172] Sebat J, Lakshmi B, Malhotra D, et al. (2007) Strong association of de novo copy number mutations with autism. Science 316: 445–449. doi: 10.1126/science.1138659
    [173] Zhao WW (2013) Intragenic deletion of RBFOX1 associated with neurodevelopmental/neuropsychiatric disorders and possibly other clinical presentations. Mol Cytogenet 6: 26. doi: 10.1186/1755-8166-6-26
    [174] Nguyen LS, Kim HG, Rosenfeld JA, et al. (2013) Contribution of copy number variants involving nonsense-mediated mRNA decay pathway genes to neuro-developmental disorders. Hum Mol Genet 22: 1816–1825. doi: 10.1093/hmg/ddt035
    [175] Talkowski ME, Rosenfeld JA, Blumenthal I, et al. (2012) Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell 149: 525–537. doi: 10.1016/j.cell.2012.03.028
    [176] Turner TN, Hormozdiari F, Duyzend MH, et al. (2016) Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. Am J Hum Genet 98: 58–74. doi: 10.1016/j.ajhg.2015.11.023
    [177] Amir RE, Van den Veyver IB, Wan M, et al. (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23: 185–188. doi: 10.1038/13810
    [178] Hanchard NA, Carvalho CM, Bader P, et al. (2012) A partial MECP2 duplication in a mildly affected adult male: a putative role for the 3' untranslated region in the MECP2 duplication phenotype. BMC Med Genet 13: 71.
    [179] Shibayama A, Cook EH Jr, Feng J, et al. (2004) MECP2 structural and 3'-UTR variants in schizophrenia, autism and other psychiatric diseases: a possible association with autism. Am J Med Genet B Neuropsychiatr Genet 128B: 50–53. doi: 10.1002/ajmg.b.30016
    [180] Helander A, Stödberg T, Jaeken J, et al. (2013) Dolichol kinase deficiency (DOLK-CDG) with a purely neurological presentation caused by a novel mutation. Mol Genet Metab 110: 342–344. doi: 10.1016/j.ymgme.2013.07.002
    [181] Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, et al. (2013) De novo mutations in epileptic encephalopathies. Nature 501: 217–221. doi: 10.1038/nature12439
    [182] McBride KL, Varga EA, Pastore MT, et al. (2010) Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly. Autism Res 3: 137–141. doi: 10.1002/aur.132
    [183] Marui T, Hashimoto O, Nanba E, et al. (2004) Association between the neurofibromatosis-1 (NF1) locus and autism in the Japanese population. Am J Med Genet B Neuropsychiatr Genet 131B: 43–47. doi: 10.1002/ajmg.b.20119
    [184] Smalley SL (1998) Autism and tuberous sclerosis. J Autism Dev Disord 28: 407–414. doi: 10.1023/A:1026052421693
    [185] Serajee FJ, Nabi R, Zhong H, et al. (2003) Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: implications for phosphatidylinositol signalling in autism. J Med Genet 40: e119. doi: 10.1136/jmg.40.11.e119
    [186] Kong A, Frigge ML, Masson G, et al. (2012) Rate of de novo mutations and the importance of father's age to disease risk. Nature 488: 471–475. doi: 10.1038/nature11396
    [187] O'Roak BJ, Vives L, Girirajan S, et al. (2012) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485: 246–250. doi: 10.1038/nature10989
    [188] Harlalka GV, Baple EL, Cross H, et al. (2013) Mutation of HERC2 causes developmental delay with Angelman-like features. J Med Genet 50: 65–73. doi: 10.1136/jmedgenet-2012-101367
    [189] Puffenberger EG, Jinks RN, Wang H, et al. (2012) A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder. Hum Mutat 33: 1639–1646. doi: 10.1002/humu.22237
    [190] Deciphering Developmental Disorders Study (2015) Large-scale discovery of novel genetic causes of developmental disorders. Nature 519: 223–228.
    [191] Nava C, Lamari F, Héron D, et al. (2012) Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE. Transl Psychiatry 2: e179. doi: 10.1038/tp.2012.102
    [192] Tastet J, Decalonne L, Marouillat S, et al. (2015) Mutation screening of the ubiquitin ligase gene RNF135 in French patients with autism. Psychiatr Genet 25: 263–267. doi: 10.1097/YPG.0000000000000100
    [193] Vourc'h P, Martin I, Bonnet-Brilhault F, et al. (2003) Mutation screening and association study of the UBE2H gene on chromosome 7q32 in autistic disorder. Psychiatr Genet 13: 221–225. doi: 10.1097/00041444-200312000-00005
    [194] Noor A, Dupuis L, Mittal K, et al. (2015) 15q11.2 duplication encompassing only the UBE3A gene is associated with developmental delay and neuropsychiatric phenotypes. HumMutat 36: 689–693.
    [195] Nurmi EL, Bradford Y, Chen Y, et al. (2001) Linkage disequilibrium at the Angelman syndrome gene UBE3A in autism families. Genomics 77: 105–113. doi: 10.1006/geno.2001.6617
    [196] Chahrour MH, Yu TW, Lim ET, et al. (2012) Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet 8: e1002635. doi: 10.1371/journal.pgen.1002635
    [197] Flex E, Ciolfi A, Caputo V, et al. (2013) Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome. J Med Genet 50: 493–499. doi: 10.1136/jmedgenet-2012-101405
    [198] Salyakina D, Cukier HN, Lee JM, et al. (2011) Copy number variants in extended autism spectrum disorder families reveal candidates potentially involved in autism risk. PLoS One 6: e26049. doi: 10.1371/journal.pone.0026049
    [199] Kato T, Tamiya G, Koyama S, et al. (2012) UBR5 gene mutation is associated with familial adult myoclonic epilepsy in a Japanese family. ISRN Neurol 2012: 508308.
    [200] Najmabadi H, Hu H, Garshasbi M, et al. (2011) Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57–63. doi: 10.1038/nature10423
    [201] Hao YH, Fountain MD Jr, FonTacer K, et al. (2015) USP7 acts as a molecular rheostat to promote WASH-dependent endosomal protein recycling and is mutated in a human neurodevelopmental disorder. Mol Cell 59: 956–969. doi: 10.1016/j.molcel.2015.07.033
    [202] Wang K, Zhang H, Ma D, et al. (2009) Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459: 528–533.
    [203] Piton A, Gauthier J, Hamdan FF, et al. (2011) Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Mol Psychiatry 16: 867–880. doi: 10.1038/mp.2010.54
    [204] De Rubeis S, He X, Goldberg AP, et al. (2014) Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515: 209–215. doi: 10.1038/nature13772
    [205] Sanders SJ, He X, Willsey AJ, et al. (2015) Insights into autism spectrum disorder genomic architecture and biology from 71 Risk Loci. Neuron 87: 1215–1233. doi: 10.1016/j.neuron.2015.09.016
    [206] Lim ET, Raychaudhuri S, Sanders SJ, et al. (2013) Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. Neuron 77: 235–242. doi: 10.1016/j.neuron.2012.12.029
    [207] Liao C, Fu F, Li R, et al. (2013) Loss-of-function variation in the DPP6 gene is associated with autosomal dominant microcephaly and mental retardation. Eur J Med Genet 56: 484–489. doi: 10.1016/j.ejmg.2013.06.008
    [208] Marshall CR, Noor A, Vincent JB, et al. (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82: 477–488. doi: 10.1016/j.ajhg.2007.12.009
    [209] Prontera P, Napolioni V, Ottaviani V, et al. (2014) DPP6 gene disruption in a family with Gilles de la Tourette syndrome. Neurogenetics 15: 237–242. doi: 10.1007/s10048-014-0418-9
    [210] Zhang Y, Manning BD (2015) mTORC1 signaling activates NRF1 to increase cellular proteasome levels. Cell Cycle 14: 2011–2017. doi: 10.1080/15384101.2015.1044188
    [211] Wang X, Proud CG (2006) The mTOR pathway in the control of protein synthesis. Physiology 21: 362–369. doi: 10.1152/physiol.00024.2006
    [212] Tilot AK, Frazier TW 2nd, Eng C (2015) Balancing proliferation and connectivity in PTEN-associated autism spectrum disorder. Neurotherapeutics 12: 609–619. doi: 10.1007/s13311-015-0356-8
    [213] Sharma A, Hoeffer CA, Takayasu Y, et al. (2010) Dysregulation of mTOR signaling in fragile X syndrome. J Neurosci 30: 694–702. doi: 10.1523/JNEUROSCI.3696-09.2010
    [214] Busquets-Garcia A, Gomis-González M, Guegan T, et al. (2013) Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat Med 19: 603–607. doi: 10.1038/nm.3127
  • Reader Comments
  • © 2017 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(5711) PDF downloads(1107) Cited by(1)

Article outline

Figures and Tables

Figures(2)  /  Tables(2)

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog