Synaptic activity regulated mRNA-silencing foci for the fine tuning of local protein synthesis at the synapse

Abstract

The regulated synthesis of specific proteins at the synapse is important for neuron plasticity, and several localized mRNAs are translated upon specific stimulus. Repression of mRNA translation is linked to the formation of mRNA-silencing foci, including Processing Bodies (PBs) and Stress Granules (SGs), which are macromolecular aggregates that harbor silenced messengers and associated proteins. In a recent work, we identified a kind of mRNA-silencing foci unique to neurons, termed S-foci, that contain the post-transcriptional regulator Smaug1/SAMD4. Upon specific synaptic stimulation, the S-foci dissolve and release mRNAs to allow their translation, paralleling the cycling of mRNAs between PBs and polysomes in other cellular contexts. Smaug 1 and other proteins involved in mRNA regulation in neurons contain aggregation domains distinct from their RNA binding motifs, and we speculate that self-aggregation helps silencing and transport. In addition to S-foci and PBs, other foci formed by distinct RNA binding proteins, such as TDP-43 and FMRP among others, respond dynamically to specific synaptic stimuli. We propose the collective name of synaptic activity-regulated mRNA silencing (SyAS) foci for these RNP aggregates that selectively respond to distinct stimulation patterns and contribute to the fine-tuning of local protein synthesis at the synapse.

Keywords: CPEB; FMRP; FUS/TLS; P-Bodies; Pumilio; RNG105; SAMD4; Smaug; TDP43; mRNA silencing; stress granules.

Figure 1. SyAS-foci and translational regulation at the synapse. (A) Several mRNA-silencing foci, including S-foci, PBs and FMRP granules, among others, are present in dendrites and dendritic spines. S-foci are different from FMRP granules and PBs. The three kind of SyAS-foci may coexist in a single dendritic spine. (B-D) Distinct SyAS-foci respond to specific stimuli, dissolving and releasing specific mRNAs. Stimulation of NMDAR or mGlutR affect S-foci and FMRP granules, and activates the translation of CamKIIα, among others.⁶ About half of synapse-localized CamKIIα mRNA is associated to S-foci under resting conditions and is released upon NMDA stimulation and S-foci dissolution.⁶ In addition, CamKIIα mRNA is as well regulated by FMRP and PBs,³⁰ opening the possibility of multiple regulation by distinct pathways. NMDAR stimulation provokes a global silencing, and the translation of a number of transcripts, including Kv1.1 mRNA among others, is repressed.^6,36