The Autistic Neuron: Troubled Translation?

Kelleher, Raymond J.; Bear, Mark F.

doi:10.1016/j.cell.2008.10.017

Cited by 538 publications

(551 citation statements)

References 63 publications

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“…Furthermore, neuronal dysfunctions are due to the modifications in synthesis level of synaptic proteins caused by a defective mRNA regulation especially translation (Kelleher & Bear, 2008). This mechanism is controlled by several genes in particular mTOR and FMR1 .…”

Section: Reviewmentioning

confidence: 99%

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Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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Section: Reviewmentioning

confidence: 99%

“…This mechanism is controlled by several genes in particular mTOR and FMR1 . FMRP protein, encoded by FMR1 gene, binds to 400 different mRNAs and represses their translation (Kelleher & Bear, 2008). The loss of FMRP protein results in fragile X syndrome that is present in 5% in patients with ASD.…”

Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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“…Recently, whole-exome studies have reported an enrichment of FMRP-associated genes in the lists of genes disrupted by RVs in ASD participants [23]. FMRP is associated with the autism candidate genes MET [116], PTEN , TSC1 , TSC2 and NF1 [117], which are also located within the PSD [118-120]. These genes are part of the phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR pathway which is activated by metabotropic glutamate receptor signaling [119,121], is an upstream effector of translation regulation, and is involved in cellular proliferation [122].…”

Section: Emerging Biological Themesmentioning

confidence: 99%

Autism genetics: searching for specificity and convergence

2012

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“…5 Therefore, dysfunctional mTORC1 signaling and dysregulated protein synthesis in neuronal cells have been associated with several neurodevelopmental disorders with intellectual disability and autism. [6][7][8][9][10][11] mTORC1 signaling modulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3, a scaffold complex that brings all components of the translation initiation process into close proximity, and by coordinating the phosphorylation and activity of key translational regulators S6K1 and 4EBP1. 12 We have recently identified two novel binding partners for eIF3, the neural Rho-GEF collybistin (CB) and the synaptic scaffold protein gephyrin, 13 which are known to be required for GABA A receptors clustering and inhibitory synapse formation.…”

Section: Introductionmentioning

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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The Autistic Neuron: Troubled Translation?

Cited by 538 publications

References 63 publications

Autism throughout genetics: Perusal of the implication of ion channels

Autism throughout genetics: Perusal of the implication of ion channels

Autism genetics: searching for specificity and convergence

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

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