On the dynamical aspects of local translation at the activated synapse

Abstract

Background The key role in the dynamic regulation of synaptic protein turnover belongs to the Fragile X Mental Retardation Protein, which regulates the efficiency of dendritic mRNA translation in response to stimulation of metabotropic glutamate receptors at excitatory synapses of the hippocampal pyramidal cells. Its activity is regulated via positive and negative regulatory loops that function in different time ranges, which is an absolute factor for the formation of chaotic regimes that lead to disrupted proteome stability. The indicated condition may cause a number of neuropsychiatric diseases, including autism and epilepsy. The present study is devoted to a theoretical analysis of the local translation system dynamic properties and identification of parameters affecting the chaotic potential of the system. Results A mathematical model that describes the maintenance of a specific pool of active receptors on the postsynaptic membrane via two mechanisms – de novo synthesis of receptor proteins and restoration of protein function during the recycling process – has been developed. Analysis of the model revealed that an increase in the values of the parameters describing the impact of protein recycling on the maintenance of a pool of active receptors in the membrane, duration of the signal transduction via the mammalian target of rapamycin pathway, influence of receptors on the translation activation, as well as reduction of the rate of synthesis and integration of de novo synthesized proteins into the postsynaptic membrane – contribute to the reduced complexity of the local translation system dynamic state. Formation of these patterns significantly depends on the complexity and non-linearity of the mechanisms of exposure of de novo synthesized receptors to the postsynaptic membrane, the correct evaluation of which is currently problematic. Conclusions The model predicts that an increase of “receptor recycling” and reduction of the rate of synthesis and integration of de novo synthesized proteins into the postsynaptic membrane contribute to the reduced complexity of the local translation system dynamic state. Herewith, stable stationary states occur much less frequently than cyclic states. It is possible that cyclical nature of functioning of the local translation system is its “normal” dynamic state.

Evolution and extinction can occur rapidly: a modeling approach

“…In a number of theoretical studies, the existence of discontinuity and phasing in the fossil record was considered as a consequence of a priori existing regulatory feedback loops - negative and positive, the combination of which led to system instability ( Robertson, 1991 ; Seaborg, 1999 ). This property of feedback regulatory loops has been noted long ago and was demonstrated in models of biological systems at various levels of their organization ( Mackey & Glass, 1977 ; Decroly & Goldbeter, 1982 ; Martinez de la Fuente et al, 1996 ; Goldbeter et al, 2001 ; Likhoshvai et al, 2014 ; Likhoshvai et al, 2015 ; Likhoshvai et al, 2016 ; Likhoshvai, Golubyatnikov & Khlebodarova, 2020 ; Harish & Hansel, 2015 ; Kogai et al, 2017 ; Khlebodarova et al, 2017 ; Khlebodarova et al, 2018 ; Khlebodarova, Kogai & Likhoshvai, 2020 ).…”

The molecular view of mechanical stress of brain cells, local translation, and neurodegenerative diseases

“…Theoretical analysis of the dynamic features of local translation system operation presented in (Khlebodarova et al, , 2020Likhoshvai, Khlebodarova, 2019) suggests that one of the possible mechanisms of neurological disorders arising under chronic mechanical stress is the abnormal hyperactivity of mTOR and local translation at the synapse. It induces the dynamic instability of de novo protein synthesis at the activated synapse.…”

“…Proceeding from the above, the activity of RAS GTPases controlling the formation and stabilization of actin filaments in dendritic spines depends directly on their de novo synthesis, i. e., on the activity of mTOR and FMRP-dependent local translation. It is conjectured that unstable local translation (Khlebodarova et al, , 2020Likhoshvai, Khlebodarova, 2019), also results in hypo-or hyperactivity of RAS, which, in turn, causes aberrations in the structure of dendritic spines and neurological disorders associated therewith (Ba et al, 2013;Pyronneau et al, 2017;Zamboni et al, 2018;Nishiyama, 2019).…”

Prediction of Translational Regulation by Network Interaction in Synaptic Plasticity Induced with Centella asiatica

“…AKT/mTOR activation has been previously associated with Alzheimer's disease (AD), with downstream targets such as 4EBP1 showing increased activity [14]. Dysfunctions in the AKT/ mTOR pathway have been identifed as risk factors for AD [15] [13]. Te fgure demonstrates the interaction of asiaticoside and betulinic acid with proteins involved in synaptic plasticity.…”

“…(a) The red boxes represent targeted proteins (TSC1 and Rheb), while the blue boxes represent the targeted pathways. (b) A modified version from Khlebodarova et al and (c) adapted from [ 13 ]. The figure demonstrates the interaction of asiaticoside and betulinic acid with proteins involved in synaptic plasticity.…”