Abstract
mRNA translation, or protein synthesis, is a major component of the transformation of the genetic code into any cellular activity. This complicated, multistep process is divided into three phases: initiation, elongation, and termination. Initiation is the step at which the ribosome is recruited to the mRNA, and is regarded as the major rate-limiting step in translation, while elongation consists of the elongation of the polypeptide chain; both steps are frequent targets for regulation, which is defined as a change in the rate of translation of an mRNA per unit time. In the normal brain, control of translation is a key mechanism for regulation of memory and synaptic plasticity consolidation, i.e., the off-line processing of acquired information. These regulation processes may differ between different brain structures or neuronal populations. Moreover, dysregulation of translation leads to pathological brain function such as memory impairment. Both normal and abnormal function of the translation machinery is believed to lead to translational up-regulation or down-regulation of a subset of mRNAs. However, the identification of these newly synthesized proteins and determination of the rates of protein synthesis or degradation taking place in different neuronal types and compartments at different time points in the brain demand new proteomic methods and system biology approaches. Here, we discuss in detail the relationship between translation regulation and memory or synaptic plasticity consolidation while focusing on a model of cortical-dependent taste learning task and hippocampal-dependent plasticity. In addition, we describe a novel systems biology perspective to better describe consolidation.
Highlights
The control of mRNA translation plays a critical role in regulating protein production; its contribution is greater than those of the modulation of mRNA synthesis, degradation, or protein turnover (Schwanhausser et al 2011)
Eukaryotic mRNAs contain a so-called cap structure at their 5′ end that includes a 7-methylguanosine moiety linked by a 5′ –5′ bond to the first nucleotide of the mRNA proper. This feature binds to eukaryotic initiation factor eIF4E and provides, in this sense, the first contact between the mRNA and components of the translational machinery (Gingras et al 1999). eIF4E in turn binds eIF4G, a scaffold protein, which binds to the poly(A)-binding protein, PABP, and eIF4A, an RNA helicase
EIF4E binds other partner proteins which, since they interact with eIF4E through a site that overlaps its binding site for eIF4G, prevent eIF4E/eIF4G binding. These include the small phosphoproteins termed eIF4E-binding proteins (4E-BPs), of which 4E-BP2 is the main isoform in the brain (Bidinosti et al 2010). 4E-BPs can be regulated by phosphorylation catalyzed by mammalian target of rapamycin complex 1, mTORC1, which results in decreased affinity of 4E-BPs for eIF4E and their release, freeing eIF4E to bind to eIF4G
Summary
Shunit Gal-Ben-Ari,1,2 Justin W. Kenney,3 Hadile Ounalla-Saad,1,2 Elham Taha,1,2 Orit David,1,2 David Levitan,1,2 Iness Gildish,1,2 Debabrata Panja,4 Balagopal Pai,4 Karin Wibrand,4 T. Ian Simpson,5 Christopher G. Proud,3 Clive R. Bramham,4 J. Douglas Armstrong,5 and Kobi Rosenblum1,2,6
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