Abstract
Protein synthesis is crucial for maintaining synaptic plasticity and synaptic signalling. Here we have attempted to understand the role of RNA binding proteins, Fragile X Mental Retardation Protein (FMRP) and Moloney Leukemia Virus 10 (MOV10) protein in N-Methyl-D-Aspartate Receptor (NMDAR) mediated translation regulation. We show that FMRP is required for translation downstream of NMDAR stimulation and MOV10 is the key specificity factor in this process. In rat cortical synaptoneurosomes, MOV10 in association with FMRP and Argonaute 2 (AGO2) forms the inhibitory complex on a subset of NMDAR responsive mRNAs. On NMDAR stimulation, MOV10 dissociates from AGO2 and promotes the translation of its target mRNAs. FMRP is required to form MOV10-AGO2 inhibitory complex and to promote translation of MOV10 associated mRNAs. Phosphorylation of FMRP appears to be the potential switch for NMDAR mediated translation and in the absence of FMRP, the distinct translation response to NMDAR stimulation is lost. Thus, FMRP and MOV10 have an important regulatory role in NMDAR mediated translation at the synapse.
Highlights
In mature neurons, protein synthesis in the dendrites and spines outweigh that of the cell body due to their sheer volume [1]
Moloney Leukemia Virus 10 (MOV10) dissociates from Argonaute 2 (AGO2) and moves to polysomes on N-Methyl-D-Aspartate Receptor (NMDAR) stimulation In order to understand the mechanism of NMDAR mediated translation, we chose to investigate the role of MOV10 because of its implication in previous studies [19, 27]
On NMDAR stimulation, there was a significant decrease in the association of MOV10 with AGO2 compared to basal (Fig. 1a) while there was no change in the levels of MOV10 on NMDAR stimulation in synaptoneurosomes (Additional file 1: Figure S1E)
Summary
Protein synthesis in the dendrites and spines outweigh that of the cell body due to their sheer volume [1]. It is important to decipher the specificity of translational response to a given neurotransmitter receptor stimulation This task has gained significance since the dysregulation of protein synthesis is thought to be a common cause for multiple neurodevelopmental disorders [5]. Glutamate is the major excitatory neurotransmitter in the mammalian brain and NMDAR and the group I metabotropic Glutamate Receptor (mGluR) are two of its primary receptors that mediate synaptic plasticity. Both NMDAR and mGluR regulate protein synthesis, group I mGluR leading to global translation activation and NMDAR to translation inhibition shown through metabolic labelling of proteins [6,7,8,9].
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