TY - JOUR

T1 - On the dynamical aspects of local translation at the activated synapse

AU - Khlebodarova, Tamara M.

AU - Kogai, Vladislav V.

AU - Likhoshvai, Vitaly A.

PY - 2020/9/14

Y1 - 2020/9/14

N2 - 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.

AB - 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.

KW - Complex dynamics

KW - FMRP

KW - Local translation

KW - Modeling

KW - mTOR pathway

KW - Synapse

KW - MAMMALIAN TARGET

KW - AUTISM

KW - MECHANISMS

KW - ENDOCYTOSIS

KW - MTOR

KW - MGLUR

KW - SIGNALING PATHWAY

KW - PLASTICITY

KW - REVEALS

UR - http://www.scopus.com/inward/record.url?scp=85090872909&partnerID=8YFLogxK

U2 - 10.1186/s12859-020-03597-0

DO - 10.1186/s12859-020-03597-0

M3 - Article

C2 - 32921299

AN - SCOPUS:85090872909

VL - 21

SP - 258

JO - BMC Bioinformatics

JF - BMC Bioinformatics

SN - 1471-2105

IS - Suppl 11

M1 - 258

ER -