Activity-dependent neuronal signalling and autism spectrum disorder

Ebert, Daniel H.; Greenberg, Michael E.

doi:10.1038/nature11860

Cited by 561 publications

(555 citation statements)

References 98 publications

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“…31 In addition, overactivated mTORC1 signaling has also been linked to the pathophysiology of non-syndromic ASD. 10,11,32,33 This hyperactivation of the mTORC1 pathway has been shown to stimulate excessive protein synthesis in neuronal cells, leading to disturbances in neuronal differentiation and morphology, synaptic connectivity, and plasticity. Loss-of-function variants in CB, which are known to reduce GABAergic transmission and alter synaptic plasticity, have been associated with overlapping phenotypes, that is, intellectual disability, epilepsy, anxiety, 15,[22][23][24][25] and now autism, present in the patient here described.…”

Section: Discussionmentioning

confidence: 99%

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

et al. 2015

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Protein synthesis regulation via mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has key roles in neural development and function, and its dysregulation is involved in neurodevelopmental disorders associated with autism and intellectual disability. mTOR regulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3 complex and by controlling phosphorylation of key translational regulators. Collybistin (CB), a neuronspecific Rho-GEF responsible for X-linked intellectual disability with epilepsy, also interacts with eIF3, and its binding partner gephyrin associates with mTOR. Therefore, we hypothesized that CB also binds mTOR and affects mTORC1 signaling activity in neuronal cells. Here, by using induced pluripotent stem cell-derived neural progenitor cells from a male patient with a deletion of entire CB gene and from control individuals, as well as a heterologous expression system, we describe that CB physically interacts with mTOR and inhibits mTORC1 signaling pathway and protein synthesis. These findings suggest that disinhibited mTORC1 signaling may also contribute to the pathological process in patients with loss-of-function variants in CB.

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Section: Discussionmentioning

confidence: 99%

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

et al. 2015

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“…Stimulation with NRG1 and BDNF in vitro renders OL myelination dependent on glutamate via NMDA receptors (Lundgaard et al, 2013), indicating that signals from growth factors and glutamate are integrated within OL‐lineage cells. Conversely, one or more growth factors could also be released with synaptic vesicles, analogous to BDNF in the context of synaptic plasticity (Ebert & Greenberg, 2013). …”

Section: Myelination and Mtormentioning

confidence: 99%

“…Specifically, mTORC1 could be recruited for myelination downstream of one or more of the growth factors discussed above, as the known signaling triggered by these factors in other cellular systems (or in SCs, in the case of NRG1) often involves mTORC1. Although mTORC1 activity is typically under control of growth factor receptors, also glutamate can activate the PI3K‐Akt‐mTORC1 signaling axis downstream of mGluRs during synaptic plasticity (Ebert & Greenberg, 2013). This raises the intriguing possibility that mTORC1 might be analogously activated by glutamate release during electrical activity‐dependent myelination and could be involved in the reported increase in MBP translation in OL processes upon glutamate release from axons (Wake et al, 2011).…”

Section: Myelination and Mtormentioning

confidence: 99%

Myelination and mTOR

Figlia

Gerber

Suter

2017

Glia

132

120

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Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is metabolically demanding and, consistent with this notion, mTORC1—a signaling hub coordinating cell metabolism—has been implicated as a key signal for myelination. Here, we will discuss metabolic aspects of myelination, illustrate the main metabolic processes regulated by mTORC1, and review advances on the role of mTORC1 in myelination of the central nervous system and the peripheral nervous system. Recent progress has revealed a complex role of mTORC1 in myelinating cells that includes, besides positive regulation of myelin growth, additional critical functions in the stages preceding active myelination. Based on the available evidence, we will also highlight potential nonoverlapping roles between mTORC1 and its known main upstream pathways PI3K‐Akt, Mek‐Erk1/2, and AMPK in myelinating cells. Finally, we will discuss signals that are already known or hypothesized to be responsible for the regulation of mTORC1 activity in myelinating cells.

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“…The defective degradation of PSD-95, a process required for synapse elimination, by the Mdm2 E3 ligase, may underlie the excessive dendritic spine number observed in Fragile X syndrome (Tsai et al, 2012). Reduced levels of the Ube3A protein levels, an E3 ligase, has also been associated with the Angelman Syndrome (Williams et al, 2010;Ebert and Greenberg, 2013). This protein is upregulated by synaptic activity thereby controlling the degradation of Arc, a protein involved in AMPAR endocytosis (Greer et al, 2010).…”

Section: Role Of Ups In Nervous Systemmentioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

112

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A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

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Activity-dependent neuronal signalling and autism spectrum disorder

Cited by 561 publications

References 98 publications

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

Myelination and mTOR

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

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