mTOR plays an important role in cow's milk allergy-associated behavioral and immunological deficits

Wu, Jackie; Theije, Caroline G. M. de; Silva, Sofia Lopes da; Horst, Hilma van der; Reinders, Margot T M; Broersen, Laus M.; Willemsen, Linette E. M.; Kas, Martien; Garssen, Johan; Kraneveld, Aletta D.

doi:10.1016/j.neuropharm.2015.04.035

Cited by 20 publications

(30 citation statements)

References 57 publications

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“…The social interaction test was performed as described. 23 In short, the WT mice (young: n = 5; middle-aged: n = 6) and TIAM2S-TG mice (young: n = 5; middle: n = 5) were individually placed in a 40 × 40 cm open field, with a small perforated Plexiglass cage (10 cm diameter) located against one wall, allowing visual, olfactory, and minimal tactile interaction. The mice were habituated to the open field for 5 minutes, and an age-and gender-matched unfamiliar target mouse was introduced in one of the cages for an additional 10 minutes.…”

Section: Animal Experimentsmentioning

confidence: 99%

TIAM2S as a novel regulator for serotonin level enhances brain plasticity and locomotion behavior

et al. 2020

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Abbreviations: CA3, cornu ammonis 3; Cdc42, cell division control protein 42 homolog; DG, dentate gyrus; GEF, guanine nucleotide exchange factor; GFAP, glial fibrillary acidic protein; HTR1B, 5-hydroxytryptamine receptor 1B; MAP-2, microtubule-associated protein 2; PARP, poly (ADP-ribose) polymerase; PDGF, platelet-derived growth factor; Rac1, Ras-related C3 botulinum toxin substrate 1; RhoA, Ras homolog gene family member A; STEF, SIF and Tiam1-like exchange factor; TIAM1/2, T cell lymphoma invasion and metastasis1/2. ABSTRACTTIAM2S, the short form of human T-cell lymphoma invasion and metastasis 2, can have oncogenic effects when aberrantly expressed in the liver or lungs. However, it is also abundant in healthy, non-neoplastic brain tissue, in which its primary function is still unknown. Here, we examined the neurobiological and behavioral significance of human TIAM2S using the human brain protein panels, a human NT2/D1-derived neuronal cell line model (NT2/N), and transgenic mice that overexpress human TIAM2S (TIAM2S-TG). Our data reveal that TIAM2S exists primarily in neurons of the restricted brain areas around the limbic system and in well-differentiated NT2/N cells. Functional studies revealed that TIAM2S has no guanine nucleotide exchange factor (GEF) activity and is mainly located in the nucleus. Furthermore, whole-transcriptome and enrichment analysis with total RNA sequencing revealed that TIAM2S-knockdown (TIAM2S-KD) was strongly associated with the cellular processes of the brain structural development and differentiation, serotonin-related signaling, and the diseases markers representing neurobehavioral developmental disorders. Moreover, TIAM2S-KD cells display decreased neurite outgrowth and reduced serotonin levels. Moreover, TIAM2S overexpressing TG mice show increased number and length of serotonergic fibers at early postnatal stage, results in higher serotonin levels at both the serum and brain regions, and higher neuroplasticity and hyperlocomotion in latter adulthood. Taken together, our results illustrate the nononcogenic functions of human TIAM2S and demonstrate that TIAM2S is a novel regulator of serotonin level, brain neuroplasticity, and locomotion behavior. K E Y W O R D Sguanine nucleotide exchange factor (GEF), hyperlocomotion, neuroplasticity, serotonergic fiber, serotonin (5-HT), TIAM2 3268 | CHU et al. | 3269CHU et al.

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Section: Animal Experimentsmentioning

confidence: 99%

TIAM2S as a novel regulator for serotonin level enhances brain plasticity and locomotion behavior

et al. 2020

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“…Single gene mutations in mammalian target of rapamycin (mTOR) signaling pathway are associated with the development of ASD and enhanced mTOR signaling plays a central role in directing immune responses toward allergy as well [255,256]. Multiple ASD syndromes are caused by mutations in genes that act to inhibit mTOR kinase, including Tsc1/Tsc2, NF1, and Pten [257].…”

Section: Immune Dysregulation or Inflammationmentioning

confidence: 99%

“…Synaptic mTOR integrates signaling from various ASD synaptic and regulatory proteins, including SHANK3, FMRP, and the glutamate receptors mGluR1/5 [257,260]. It has been proposed that mTOR pathway plays a central role in directing immune responses toward allergy (e.g., cow's milk allergy, or valproic acid exposure) as well, and may be a pivotal link between the immune disturbances and behavioral deficits observed in ASD [233,261,262]. Inhibition of mTORC1 activity by rapamycin improved the behavioral and immunological deficits of cow's milk allergic mice [256].…”

Section: Immune Dysregulation or Inflammationmentioning

confidence: 99%

“…It has been proposed that mTOR pathway plays a central role in directing immune responses toward allergy (e.g., cow's milk allergy, or valproic acid exposure) as well, and may be a pivotal link between the immune disturbances and behavioral deficits observed in ASD [233,261,262]. Inhibition of mTORC1 activity by rapamycin improved the behavioral and immunological deficits of cow's milk allergic mice [256]. And also, sulindac (nonsteroidal anti-inflammatory drugs) by suppression of the Wnt signaling pathway relieves autistic-like behaviors partially by deactivating the mTOR-signaling pathway in valproic acid-exposed rats [233].…”

Section: Immune Dysregulation or Inflammationmentioning

confidence: 99%

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The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

Carrascosa-Romero¹,

Cabo²

2017

Autism - Paradigms, Recent Research and Clinical Applications

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The prevalence of autism has increased in an exponential way in the past few years. Many monogenetic mutations as well as copy number variants and single nucleotide polymorphisms have been associated with autism spectrum disorders (ASD), a large proportion of which occur in genes associated with synaptogenesis and synaptic function. However, the increase in appearance of genetic alterations does not explain the etiology of an elevated number of ASD cases. Recent research is now focusing on the role of environmental/epigenetic factors, which by themselves and/or in combination with classical genetic factors, may be the root cause of a large number of ASDs. In this chapter we review the current literature regarding the epigenetic changes involved in ASD, including their possible mechanisms of action such as oxidative stress, altered fatty acid metabolism, mitochondrial dysfunction, DNA methylation and histone methylation (via the one-carbon metabolism cycle), histone variants, and ATP-dependent chromatin remodeling. We discuss possible new biochemical markers related to autism as well as new lines of research for therapeutic targets.

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“…Долгое время эти диеты не находили поддержки у врачей и исследователей аутизма, но в последнее время положение изменилось. Было показано, что сигнальный путь mTOR также связан с индуцируемыми пищевой аллергией поведенческими и иммунологическими нарушениями (Wu et al, 2015). У орально сенсибилизированных модельных мышей была вызвана аллергическая реакция на молочную сыворотку, которая приводила к снижению социального взаимодействия и нарастанию повторяющегося поведения.…”

Section: нарушение регуляции сигнального пути Mtor как связующее звенunclassified

Molecular mechanisms of autism as a form of synaptic dysfunction

Trifonova¹,

Khlebodarova²,

Грунтенко³

2016

Vestn. VOGiS

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Autism spectrum disorders are a separate group of defects with a very high genetic component. Genetic screening has identified hundreds of mutations and other genetic variations associated with autism, and bioinformatic analysis of signaling pathways and gene networks has led to understanding that many of these mutational changes are involved in the functioning of synapses. A synapse is a site of electrochemical communication between neurons and an essential subunit for learning and memory. Interneuronal com municative relationships are plastic. The most promin ent forms of synaptic plasticity are accompanied by changes in protein biosynthesis, both in neuron body and in dendrites. Protein biosynthesis or translation is a carefully regulated process, with a central role played by mTOR (mammalian or mechanistic target of rapamycin). Normally mTORregulated translation is slightly inhibited, and in most cases mutational damage to at least one of the links of the mTOR sig naling pathway, increases translation and leads to impaired synaptic plasticity and behavior. Deregula tion of the local translation in dendrites is connected with the following monogenic autism spectrum disorders: neurofibromatosis type 1, Noonan synd ro me, Costello syndrome, Cowden syndrome, tuberous sclerosis, fragile X chromosome, syndrome, and Rett syndrome. The review considers the most important mutations leading to monogenic autism, as well as the possibility of a mechanismbased treatment of certain disorders of the autism spectrum.

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mTOR plays an important role in cow's milk allergy-associated behavioral and immunological deficits

Cited by 20 publications

References 57 publications

TIAM2S as a novel regulator for serotonin level enhances brain plasticity and locomotion behavior

TIAM2S as a novel regulator for serotonin level enhances brain plasticity and locomotion behavior

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

Molecular mechanisms of autism as a form of synaptic dysfunction

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