mTOR信号通路在孤独症谱系障碍中的研究进展
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摘要
哺乳动物雷帕霉素靶蛋白(mTOR)为细胞内信号通路转导分子,调节很多重要的生理过程。m TOR信号通路在神经系统的突触可塑性、信息传递和加工、神经调控等方面发挥重要作用。mTOR信号通路失调被认为与孤独症谱系障碍(ASD)的发病机制有关,mTOR抑制剂可以改善ASD的症状。本文对m TOR信号通路在ASD发病机制中的作用进行综述,以期为ASD的靶向治疗提供理论依据。[中国当代儿科杂志,2019,21(7):718-723]
Mammalian target of rapamycin(mTOR) is an intracellular signaling pathway molecule which regulates various fundamental physiological processes. The mTOR signaling pathway plays an important role in synaptic plasticity,information transmission and processing,and neuroregulation. Dysregulation of the mTOR signaling pathway is generally considered to be related to the pathogenesis of autism spectrum disorder(ASD); meanwhile,the mTOR inhibitor can ameliorate the symptoms of ASD. The role of mTOR in the pathogenesis of ASD is summarized in this article to provide a theoretical basis for targeted therapy of ASD. [Chin J Contemp Pediatr,2019,21(7):718-723]
Mammalian target of rapamycin(mTOR) is an intracellular signaling pathway molecule which regulates various fundamental physiological processes. The mTOR signaling pathway plays an important role in synaptic plasticity,information transmission and processing,and neuroregulation. Dysregulation of the mTOR signaling pathway is generally considered to be related to the pathogenesis of autism spectrum disorder(ASD); meanwhile,the mTOR inhibitor can ameliorate the symptoms of ASD. The role of mTOR in the pathogenesis of ASD is summarized in this article to provide a theoretical basis for targeted therapy of ASD. [Chin J Contemp Pediatr,2019,21(7):718-723]
引文
[1]Sun X,Allison C,Wei L,et al.Autism prevalence in China is comparable to Western prevalence[J].Mol Autism,2019,10:7.
[2]Chaste P,Leboyer M.Autism risk factors:genes,environment,and gene-environment interactions[J].Dialogues Clin Neurosci,2012,14(3):281-292.
[3]Saxton RA,Sabatini DM.mTOR signaling in growth,metabolism,and disease[J].Cell,2017,168(6):960-976.
[4]Yan J,Porch MW,Court-Vazquez B,et al.Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice[J].Proc Natl Acad Sci U S A,2018,115(41):E9707-E9716.
[5]Rosina E,Battan B,Siracusano M,et al.Disruption of mTORand MAPK pathways correlates with severity in idiopathic autism[J].Transl Psychiatry,2019,9(1):50.
[6]Onore C,Yang H,Van de Water J,et al.Dynamic Akt/mTORsignaling in children with autism spectrum disorder[J].Front Pediatr,2017,5:43.
[7]Huber KM,Klann E,Costa-Mattioli M,et al.Dysregulation of mammalian target of rapamycin signaling in mouse models of autism[J].J Neurosci,2015,35(41):13836-13842.
[8]Switon K,Kotulska K,Janusz-Kaminska A,et al.Molecular neurobiology of mTOR[J].Neuroscience,2017,341:112-153.
[9]Garg S,Green J.Studying child development in genetic models of ASD[J].Prog Brain Res,2018,241:159-192.
[10]Caglayan AO.Genetic causes of syndromic and non-syndromic autism[J].Dev Med Child Neurol,2010,52(2):130-138.
[11]Tsai PT,Hull C,Chu Y,et al.Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice[J].Nature,2012,488(7413):647-651.
[12]Schneider M,de Vries PJ,Sch?nig K,et al.mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus[J].Eur Arch Psychiatry Clin Neurosci,2017,267(5):455-463.
[13]Kilincaslan A,Kok BE,Tekturk P,et al.Beneficial effects of everolimus on autism and attention-deficit/hyperactivity disorder symptoms in a group of patients with tuberous sclerosis complex[J].J Child Adolesc Psychopharmacol,2017,27(4):383-388.
[14]Lee YR,Chen M,Pandolfi PP.The functions and regulation of the PTEN tumour suppressor:new modes and prospects[J].Nat Rev Mol Cell Biol,2018,19(9):547-562.
[15]Kwon CH,Luikart BW,Powell CM,et al.PTEN regulates neuronal arborization and social interaction in mice[J].Neuron,2006,50(3):377-388.
[16]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].JNeurosci,2009,29(6):1773-1783.
[17]Yeung KS,Tso WWY,Ip JJK,et al.Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism[J].Mol Autism,2017,8:66.
[18]Darnell JC,Van Driesche SJ,Zhang C,et al.FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism[J].Cell,2011,146(2):247-261.
[19]Kazdoba TM,Leach PT,Silverman JL,et al.Modeling fragile Xsyndrome in the Fmr1 knockout mouse[J].Intractable Rare Dis Res,2014,3(4):118-133.
[20]Tian Y,Yang C,Shang S,et al.Loss of FMRP impaired hippocampal long-term plasticity and spatial learning in rats[J].Front Mol Neurosci,2017,10:269.
[21]McKinney BC,Grossman AW,Elisseou NM,et al.Dendritic spine abnormalities in the occipital cortex of C57BL/6 Fmr1knockout mice[J].Am J Med Genet B Neuropsychiatr Genet,2005,136B(1):98-102.
[22]Sharma A,Hoeffer CA,Takayasu Y,et al.Dysregulation of mTOR signaling in fragile X syndrome[J].J Neurosci,2010,30(2):694-702.
[23]Ronesi JA,Collins KA,Hays SA,et al.Disrupted homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome[J].Nat Neurosci,2012,15(3):431-440,S1.
[24]Bhattacharya A,Kaphzan H,Alvarez-Dieppa AC,et al.Genetic removal of p70 S6 kinase 1 corrects molecular,synaptic,and behavioral phenotypes in fragile X syndrome mice[J].Neuron,2012,76(2):325-337.
[25]Gkogkas CG,Khoutorsky A,Cao R,et al.Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes[J].Cell Rep,2014,9(5):1742-1755.
[26]Bilder DA,Bakian AV,Stevenson DA,et al.Brief report:the prevalence of neurofibromatosis type 1 among children with autism spectrum disorder identified by the autism and developmental disabilities monitoring network[J].J Autism Dev Disord,2016,46(10):3369-3376.
[27]Borrie SC,Brems H,Legius E,et al.Cognitive dysfunctions in intellectual disabilities:the contributions of the Ras-MAPKand PI3K-AKT-mTOR pathways[J].Annu Rev Genomics Hum Genet,2017,18:115-142.
[28]Weiss B,Widemann BC,Wolters P,et al.Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas:a neurofibromatosis clinical trials consortium phase II study[J].Neuro Oncol,2015,17(4):596-603.
[29]Franz DN,Agricola K,Mays M,et al.Everolimus for subependymal giant cell astrocytoma:5-year final analysis[J].Ann Neurol,2015,78(6):929-938.
[30]Codina-SolàM,Rodríguez-Santiago B,Homs A,et al.Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders[J].Mol Autism,2015,6:21.
[31]Magdalon J,Sánchez-Sánchez SM,Griesi-Oliveira K,et al.Dysfunctional mTORC1 signaling:a convergent mechanism between syndromic and nonsyndromic forms of autism spectrum disorder?[J].Int J Mol Sci,2017,18(3).pii:E659.
[32]Tang G,Gudsnuk K,Kuo SH,et al.Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits[J].Neuron,2014,83(5):1131-1143.
[33]Poopal AC,Schroeder LM,Horn PS,et al.Increased expression of the PI3K catalytic subunit p110δunderlies elevated S6phosphorylation and protein synthesis in an individual with autism from a multiplex family[J].Mol Autism,2016,7:3.
[34]Jiang HY,Xu LL,Shao L,et al.Maternal infection during pregnancy and risk of autism spectrum disorders:a systematic review and meta-analysis[J].Brain Behav Immun,2016,58:165-172.
[35]Solek CM,Farooqi N,Verly M,et al.Maternal immune activation in neurodevelopmental disorders[J].Dev Dyn,2018,247(4):588-619.
[36]Bilbo SD,Block CL,Bolton JL,et al.Beyond infectionmaternal immune activation by environmental factors,microglial development,and relevance for autism spectrum disorders[J].Exp Neurol,2018,299(Pt A):241-251.
[37]Smith SE,Elliott RM,Anderson MP.Maternal immune activation increases neonatal mouse cortex thickness and cell density[J].J Neuroimmune Pharmacol,2012,7(3):529-532.
[38]Fernández de Cossío L,Guzmán A,van der Veldt S,et al.Prenatal infection leads to ASD-like behavior and altered synaptic pruning in the mouse offspring[J].Brain Behav Immun,2017,63:88-98.
[39]Estes ML,McAllister AK.Maternal immune activation:implications for neuropsychiatric disorders[J].Science,2016,353(6301):772-777.
[40]Lombardo MV,Moon HM,Su J,et al.Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder[J].Mol Psychiatry,2018,23(4):1001-1013.
[41]Amodeo DA,Lai CY,Hassan O,et al.Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex[J].Neurobiol Dis,2019,125:211-218.
[42]Siuta MA,Robertson SD,Kocalis H,et al.Dysregulation of the norepinephrine transporter sustains cortical hypodopaminergia and schizophrenia-like behaviors in neuronal rictor null mice[J].PLoS Biol,2010,8(6):e1000393.
[43]Smith V,Brown N.Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism[J].Arch Dis Child Educ Pract Ed,2014,99(5):198.
[44]Qin L,Dai X,Yin Y.Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats[J].Mol Cell Neurosci,2016,75:27-35.
[45]Tartaglione AM,Schiavi S,Calamandrei G,et al.Prenatal valproate in rodents as a tool to understand the neural underpinnings of social dysfunctions in autism spectrum d i s o r d e r[J].N e u r o p h a r m a c o l o g y,2 0 1 9.p i i:S 0 0 2 8-3908(18)30913-4.doi:10.1016/j.neuropharm.2018.12.024.[Epub ahead of print]
[46]Kotajima-Murakami H,Kobayashi T,Kashii H,et al.Effects of rapamycin on social interaction deficits and gene expression in mice exposed to valproic acid in utero[J].Mol Brain,2019,12(1):3.
[47]French JA,Lawson JA,Yapici Z,et al.Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis(EXIST-3):a phase 3,randomised,double-blind,placebo-controlled study[J].Lancet,2016,388(10056):2153-2163.
[2]Chaste P,Leboyer M.Autism risk factors:genes,environment,and gene-environment interactions[J].Dialogues Clin Neurosci,2012,14(3):281-292.
[3]Saxton RA,Sabatini DM.mTOR signaling in growth,metabolism,and disease[J].Cell,2017,168(6):960-976.
[4]Yan J,Porch MW,Court-Vazquez B,et al.Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice[J].Proc Natl Acad Sci U S A,2018,115(41):E9707-E9716.
[5]Rosina E,Battan B,Siracusano M,et al.Disruption of mTORand MAPK pathways correlates with severity in idiopathic autism[J].Transl Psychiatry,2019,9(1):50.
[6]Onore C,Yang H,Van de Water J,et al.Dynamic Akt/mTORsignaling in children with autism spectrum disorder[J].Front Pediatr,2017,5:43.
[7]Huber KM,Klann E,Costa-Mattioli M,et al.Dysregulation of mammalian target of rapamycin signaling in mouse models of autism[J].J Neurosci,2015,35(41):13836-13842.
[8]Switon K,Kotulska K,Janusz-Kaminska A,et al.Molecular neurobiology of mTOR[J].Neuroscience,2017,341:112-153.
[9]Garg S,Green J.Studying child development in genetic models of ASD[J].Prog Brain Res,2018,241:159-192.
[10]Caglayan AO.Genetic causes of syndromic and non-syndromic autism[J].Dev Med Child Neurol,2010,52(2):130-138.
[11]Tsai PT,Hull C,Chu Y,et al.Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice[J].Nature,2012,488(7413):647-651.
[12]Schneider M,de Vries PJ,Sch?nig K,et al.mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus[J].Eur Arch Psychiatry Clin Neurosci,2017,267(5):455-463.
[13]Kilincaslan A,Kok BE,Tekturk P,et al.Beneficial effects of everolimus on autism and attention-deficit/hyperactivity disorder symptoms in a group of patients with tuberous sclerosis complex[J].J Child Adolesc Psychopharmacol,2017,27(4):383-388.
[14]Lee YR,Chen M,Pandolfi PP.The functions and regulation of the PTEN tumour suppressor:new modes and prospects[J].Nat Rev Mol Cell Biol,2018,19(9):547-562.
[15]Kwon CH,Luikart BW,Powell CM,et al.PTEN regulates neuronal arborization and social interaction in mice[J].Neuron,2006,50(3):377-388.
[16]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].JNeurosci,2009,29(6):1773-1783.
[17]Yeung KS,Tso WWY,Ip JJK,et al.Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism[J].Mol Autism,2017,8:66.
[18]Darnell JC,Van Driesche SJ,Zhang C,et al.FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism[J].Cell,2011,146(2):247-261.
[19]Kazdoba TM,Leach PT,Silverman JL,et al.Modeling fragile Xsyndrome in the Fmr1 knockout mouse[J].Intractable Rare Dis Res,2014,3(4):118-133.
[20]Tian Y,Yang C,Shang S,et al.Loss of FMRP impaired hippocampal long-term plasticity and spatial learning in rats[J].Front Mol Neurosci,2017,10:269.
[21]McKinney BC,Grossman AW,Elisseou NM,et al.Dendritic spine abnormalities in the occipital cortex of C57BL/6 Fmr1knockout mice[J].Am J Med Genet B Neuropsychiatr Genet,2005,136B(1):98-102.
[22]Sharma A,Hoeffer CA,Takayasu Y,et al.Dysregulation of mTOR signaling in fragile X syndrome[J].J Neurosci,2010,30(2):694-702.
[23]Ronesi JA,Collins KA,Hays SA,et al.Disrupted homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome[J].Nat Neurosci,2012,15(3):431-440,S1.
[24]Bhattacharya A,Kaphzan H,Alvarez-Dieppa AC,et al.Genetic removal of p70 S6 kinase 1 corrects molecular,synaptic,and behavioral phenotypes in fragile X syndrome mice[J].Neuron,2012,76(2):325-337.
[25]Gkogkas CG,Khoutorsky A,Cao R,et al.Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes[J].Cell Rep,2014,9(5):1742-1755.
[26]Bilder DA,Bakian AV,Stevenson DA,et al.Brief report:the prevalence of neurofibromatosis type 1 among children with autism spectrum disorder identified by the autism and developmental disabilities monitoring network[J].J Autism Dev Disord,2016,46(10):3369-3376.
[27]Borrie SC,Brems H,Legius E,et al.Cognitive dysfunctions in intellectual disabilities:the contributions of the Ras-MAPKand PI3K-AKT-mTOR pathways[J].Annu Rev Genomics Hum Genet,2017,18:115-142.
[28]Weiss B,Widemann BC,Wolters P,et al.Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas:a neurofibromatosis clinical trials consortium phase II study[J].Neuro Oncol,2015,17(4):596-603.
[29]Franz DN,Agricola K,Mays M,et al.Everolimus for subependymal giant cell astrocytoma:5-year final analysis[J].Ann Neurol,2015,78(6):929-938.
[30]Codina-SolàM,Rodríguez-Santiago B,Homs A,et al.Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders[J].Mol Autism,2015,6:21.
[31]Magdalon J,Sánchez-Sánchez SM,Griesi-Oliveira K,et al.Dysfunctional mTORC1 signaling:a convergent mechanism between syndromic and nonsyndromic forms of autism spectrum disorder?[J].Int J Mol Sci,2017,18(3).pii:E659.
[32]Tang G,Gudsnuk K,Kuo SH,et al.Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits[J].Neuron,2014,83(5):1131-1143.
[33]Poopal AC,Schroeder LM,Horn PS,et al.Increased expression of the PI3K catalytic subunit p110δunderlies elevated S6phosphorylation and protein synthesis in an individual with autism from a multiplex family[J].Mol Autism,2016,7:3.
[34]Jiang HY,Xu LL,Shao L,et al.Maternal infection during pregnancy and risk of autism spectrum disorders:a systematic review and meta-analysis[J].Brain Behav Immun,2016,58:165-172.
[35]Solek CM,Farooqi N,Verly M,et al.Maternal immune activation in neurodevelopmental disorders[J].Dev Dyn,2018,247(4):588-619.
[36]Bilbo SD,Block CL,Bolton JL,et al.Beyond infectionmaternal immune activation by environmental factors,microglial development,and relevance for autism spectrum disorders[J].Exp Neurol,2018,299(Pt A):241-251.
[37]Smith SE,Elliott RM,Anderson MP.Maternal immune activation increases neonatal mouse cortex thickness and cell density[J].J Neuroimmune Pharmacol,2012,7(3):529-532.
[38]Fernández de Cossío L,Guzmán A,van der Veldt S,et al.Prenatal infection leads to ASD-like behavior and altered synaptic pruning in the mouse offspring[J].Brain Behav Immun,2017,63:88-98.
[39]Estes ML,McAllister AK.Maternal immune activation:implications for neuropsychiatric disorders[J].Science,2016,353(6301):772-777.
[40]Lombardo MV,Moon HM,Su J,et al.Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder[J].Mol Psychiatry,2018,23(4):1001-1013.
[41]Amodeo DA,Lai CY,Hassan O,et al.Maternal immune activation impairs cognitive flexibility and alters transcription in frontal cortex[J].Neurobiol Dis,2019,125:211-218.
[42]Siuta MA,Robertson SD,Kocalis H,et al.Dysregulation of the norepinephrine transporter sustains cortical hypodopaminergia and schizophrenia-like behaviors in neuronal rictor null mice[J].PLoS Biol,2010,8(6):e1000393.
[43]Smith V,Brown N.Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism[J].Arch Dis Child Educ Pract Ed,2014,99(5):198.
[44]Qin L,Dai X,Yin Y.Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats[J].Mol Cell Neurosci,2016,75:27-35.
[45]Tartaglione AM,Schiavi S,Calamandrei G,et al.Prenatal valproate in rodents as a tool to understand the neural underpinnings of social dysfunctions in autism spectrum d i s o r d e r[J].N e u r o p h a r m a c o l o g y,2 0 1 9.p i i:S 0 0 2 8-3908(18)30913-4.doi:10.1016/j.neuropharm.2018.12.024.[Epub ahead of print]
[46]Kotajima-Murakami H,Kobayashi T,Kashii H,et al.Effects of rapamycin on social interaction deficits and gene expression in mice exposed to valproic acid in utero[J].Mol Brain,2019,12(1):3.
[47]French JA,Lawson JA,Yapici Z,et al.Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis(EXIST-3):a phase 3,randomised,double-blind,placebo-controlled study[J].Lancet,2016,388(10056):2153-2163.