Abstract
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 neuron-specific 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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Acknowledgements
We are grateful to all of the subjects who participated in this work. We thank Elaine Cristina Zachi for performing formal psychological evaluation of the patient. We thank Marta Diniz and Andressa Morales for technical assistance. We thank Soely Moura, Aline Moraes, and Constância G Urbani for secretarial assistance. This work was supported by grants from CNPq (National Counsel of Technological and Scientific Development), FAPESP (São Paulo Research Foundation), CAPES (Higher Education Co-Ordination Agency), and Autismo and Realidade.
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Machado, C., Griesi-Oliveira, K., Rosenberg, C. et al. Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism. Eur J Hum Genet 24, 59–65 (2016). https://doi.org/10.1038/ejhg.2015.69
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DOI: https://doi.org/10.1038/ejhg.2015.69
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