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

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 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.

Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum disorder

“…So far, 11 patients with deletions, point mutations and rearrangements involving ARHGEF9 gene have been described (de Ligt et al, 2012;Harvey et al, 2004;Kalscheuer et al, 2009;Lemke et al, 2012;Lesca et al, 2011;Machado et al, 2016;Marco et al, 2008;Shimojima et al, 2011). The clinical features are summarized in Table 1.…”

“…Gephyrin is a key protein of the scaffolding system of inhibitory synapses that is essential for postsynaptic clustering of both GABA and glycine receptors (Tretter et al, 2012). Collybistin was recently shown to be involved in downregulation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, similar to gephyrin (Machado et al, 2016). Thereupon, increased mTORC1 activity has been proposed to contribute to the phenotype of intellectual disability and ASD in ARHGEF9 mutated patients.…”

“…Autism spectrum disorder associated with ARHGEF9 was recently described (Machado et al, 2016) in an 18 year old male with a 216.7 kb de novo Xq11.1 deletion. Our patient has the smallest deletion in this region reported thus far (Fig.…”

Progress in the molecular mechanisms of genetic epilepsies using patient‐induced pluripotent stem cells

“…Thus, iPSCs can provide a reliable platform for the study of the molecular mechanisms of GE. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Studies using iPSC technology to investigate the molecular mechanisms of GE have included studies focusing on Rett syndrome, Dravet syndrome, Phelan-McDermid syndrome (PMDS), and fragile X syndrome (FxS). Classic GE syndromes include childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic-clonic seizures alone (GTCS).…”

Evaluation of molecular markers in osteogenic differentiation of mesenchymal stem cells

“…However, it is still unclear if the osteopotential properties vary depending on the cell source used for cell reprogrammation by the pluripotency factors.1.5 iPSCs as tool for in vitro disease modelingMost of the knowledge on the mechanisms of human genetic diseases has been based on mouse models. This biological system approach have been considered the golden standard for modeling in vivo human disease, but the species-specific differences between mice and humans related to physiological, biochemical, molecular and anatomical aspects have prompt the search for new methods to model human diseases(Tiscornia et al 2011).iPSCs have recently arisen as a new promising option to model human diseases in vitro and there are currently several successful examples such as studies of mechanisms related to Alzheimer´s disease (Israel et al, 2012; Yagi et al, 2011), Cardiotoxicity (Cohen et al, 2011), Down syndrome (Shi et al, 2012), Fragile X syndrome (Sheridan et al, 2011), Parkinson´s disease (Byers et al, 2011; Devine et al, 2011; Sanchez-Danes et al, 2012), Diabetes, Types 1 and 2 (Maehr et al, 2009; Ohmine et al, 2012), Multiple sclerosis(Song et al, 2012), Rett syndrome(Ananiev et al, 2011), autism spectrum disorders(Griesi-Oliveira et al, 2013;Machado et al, 2016) and many others. It would be also invaluable to model craniofacial disorders, as cranial human development is quite peculiar and might involve species-specific signaling.One main advantage of cell reprogramming is that it enables the study and analysis of a specific disease(Figure 8), including rare disorders and syndromes in which the involvement of the individual's genome containing disease-specific alterations is mandatory(Trounson et al, 2012).…”