Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders

Abstract

Autism spectrum disorder (ASD) is a heterogeneous group of heritable neurodevelopmental disorders. Symptoms of ASD, which include deficits in social interaction skills, impaired communication ability, and ritualistic-like repetitive behaviors, appear in early childhood and continue throughout life. Genetic studies have revealed at least two clusters of genes frequently associated with ASD and intellectual disability: those encoding proteins involved in translational control and those encoding proteins involved in synaptic function. We hypothesize that mutations occurring in these two clusters of genes interfere with interconnected downstream signaling pathways in neuronal cells to cause ASD symptomatology. In this review, we discuss the monogenic forms of ASD caused by mutations in genes encoding for proteins that regulate translation and synaptic function. Specifically, we describe the function of these proteins, the intracellular signaling pathways that they regulate, and the current mouse models used to characterize the synaptic and behavioral features associated with their mutation. Finally, we summarize recent studies that have established a connection between mRNA translation and synaptic function in models of ASD and propose that dysregulation of one has a detrimental impact on the other.

Figure 1. Schematic of the hypothetical connection between protein synthesis and synaptic proteins

Activation of group I mGluR receptors results in the activation of mTORC1 signaling, which increases protein synthesis. mTORC1 phosphorylates S6K1 and 4E-BP2.; phosphorylation of 4E-BP2 release eIF4E and results in the association of eIF4E with eIF4G to form of the active eIF4F (eIF4E-eIF4G-eIF4A) complex. eIF4F promotes the binding of mRNAs to ribosomes and recruits Mnk, which phosphorylates eIF4E, and eIF4B, which is phosphorylated by S6K1. The eIF4F complex and the poly(A) tail act synergistically together with MnK-dependent phosphorylation of eIF4E to stimulate cap-dependent translation initiation. Cap-dependent protein synthesis translates some mRNAs that encode for synaptic proteins located in the PSD. It is possible that mutation in genes encoding for proteins involved in the regulation of the mTORC1 pathway results in aberrant synthesis synaptic proteins such as neuroligins, SHANK, SAPAP, etc. The altered synthesis of these proteins would generate changes in molecular, structural, and synaptic plasticity, ultimately leading to ASD pathophysiology. The protein products of genes associated with ASD are circled in red.

Figure 2. Schematic of the hypothetical connection between synaptic proteins and protein synthesis

Intracellular signal transduction is initiated by the activation of neurotransmitter receptors that are organized with scaffolding proteins and adhesion molecules in the PSD. Receptor stimulation triggers the activation of intracellular signaling cascades including the mTORC1 and ERK pathways, which results in increased translation (see also Fig1). Given the importance of synaptic proteins in this type of signal transduction, mutations affecting genes encoding for these proteins could result in abnormal signaling that ultimately results in aberrant protein synthesis. The protein products of genes associated with ASD are circled in red.