Dynamic landscape of the local translation at activated synapses

Abstract

The mammalian target of rapamycin (mTOR) signaling pathway is the central regulator of cap-dependent translation at the synapse. Disturbances in mTOR pathway have been associated with several neurological diseases, such as autism and epilepsy. RNA-binding protein FMRP, a negative regulator of translation initiation, is one of the key components of the local translation system. Activation and inactivation of FMRP occurs via phosphorylation by S6 kinase and dephosphorylation by PP2A phosphatase, respectively. S6 kinase and PP2A phosphatase are activated in response to mGluR receptor stimulation through different signaling pathways and at different rates. The dynamic aspects of this system are poorly understood. We developed a mathematical model of FMRP-dependent regulation of postsynaptic density (PSD) protein synthesis in response to mGluR receptor stimulation and conducted in silico experiments to study the regulatory circuit functioning. The modeling results revealed the possibility of generating oscillatory (cyclic and quasi-cyclic), chaotic and even hyperchaotic dynamics of postsynaptic protein synthesis as well as the presence of multiple attractors in a wide range of parameters of the local translation system. The results suggest that autistic disorders associated with mTOR pathway hyperactivation may be due to impaired proteome stability associated with the formation of complex dynamic regimes of PSD protein synthesis in response to stimulation of mGluR receptors on the postsynaptic membrane of excitatory synapses on pyramidal hippocampal cells.

The mTOR Signaling Pathway Activity and Vitamin D Availability Control the Expression of Most Autism Predisposition Genes

“…Previously, we conducted in silico experiments and showed that increased activity of the mTOR pathway might result in generating oscillatory (cyclic and quasi-cyclic), chaotic, and even hyperchaotic dynamics of FMRP-dependent postsynaptic protein synthesis. Our results suggested that ASD associated with mTOR pathway hyperactivation might be due to impaired proteome stability associated with complex dynamic regimes of protein synthesis in response to stimulation of mGluR receptors of excitatory synapses [28]. It is highly possible that any mutation in postsynaptic mTOR-or FMRP-targets additionally perturbs proteostasis and worsens autistic phenotype under the condition of mTOR pathway hyperactivation.…”

ASDmiR: A Stepwise Method to Uncover miRNA Regulation Related to Autism Spectrum Disorder

“…Disease and functional enrichment analysis indicate that the top 20 largest miRNA–target regulatory modules are significantly enriched in 397 GO terms, 3 KEGG pathways, 12 Reactome pathways, and 69 DisGeNET terms. Specifically, several biological processes, pathways, and diseases, including anxiety disorder (umls: C0003469) ( White et al, 2009 ), Alternative mRNA splicing (GO: 0000380) ( Quesnel-Vallieres et al, 2019 ), circadian rhythm (GO: 0007623) ( Hu et al, 2017 ), and mTOR signaling pathway (R-HSA-165159) ( Khlebodarova et al, 2018 ) are closely related to ASD ( Table 1 ).…”

Selective targeting of mRNA and following protein synthesis of CaMKIIα at the long-term potentiation-induced site

“…In Drosophila, local translation of Camk2 mRNA is controlled by a balance between RISC, a component of RNA interference, and proteasome, which works for degradation of RISC (Ashraf et al, 2006). These accurate regulations of local translation probably increase signal and noise ratio of synapses to establish circuits for cognitive functions, on the other hand, disruption of the system may link to cognitive impairments and neuropsychiatric disorders (Khlebodarova et al, 2018).…”