Abstract:The production of proteins from mRNAs localized at the synapse ultimately controls the strength of synaptic transmission, thereby affecting behavior and cognitive functions. The regulated transcription, processing, and transport of mRNAs provide dynamic control of the dendritic transcriptome, which includes thousands of messengers encoding multiple cellular functions. Translation is locally modulated by synaptic activity through a complex network of RNA-binding proteins (RBPs) and various types of non-coding R… Show more
“…NMDAR stimulation globally inhibits dendritic protein synthesis with consequences for translation specificity (reviewed in Thomas et al, 2014). Here, we show that the translational silencing upon exposure to NMDA is linked to the formation of synaptic XRN1-positive bodies, which are novel post-synaptic bodies that contain XRN1 and apparently lack decapping activity and that we termed SX-bodies.…”
Section: Discussionmentioning
confidence: 84%
“…RNA molecules might contribute to the stability of RNP liquid droplets by serving as a platform for multiple binding, and we found that RNA breakdown affects SX-body integrity. Additional cohesive forces that might help the condensation of RNP liquid droplets depend on homotypic and heterotypic protein-protein interaction mediated largely by low complexity regions (LCRs) Kato et al, 2012;Brangwynne, 2013;Jonas and Izaurralde, 2013;Thomas et al, 2014). The XRN1 C-terminus displays several LCRs, some of them rich in proline, and we speculate that these LCRs are likely to play a role in SX-body aggregation (Fig.…”
Section: What Is the Nature Of The Sx-bodies?mentioning
Repression of mRNA translation is linked to the formation of specific cytosolic foci such as stress granules and processing bodies, which store or degrade mRNAs. In neurons, synaptic activity regulates translation at the post-synapse and this is important for plasticity. Nmethyl-D-aspartate (NMDA) receptor stimulation downregulates translation, and we speculate that this is linked to the formation of unknown mRNA-silencing foci. Here, we show that the 59-39 exoribonuclease XRN1 forms discrete clusters associated with the post-synapse that are different from processing bodies or stress granules, and we named them synaptic XRN1 bodies (SX-bodies). Using primary neurons, we found that the SX-bodies respond to synapse stimulation and that their formation correlates inversely with the local translation rate. SX-bodies increase in size and number upon NMDA stimulation, and metabotropic glutamate receptor activation provokes SX-body dissolution, along with increased translation. The response is specific and the previously described Smaug1 foci and FMRP granules show a different response. Finally, XRN1 knockdown impairs the translational repression triggered by NMDA. Collectively, these observations support a role for the SX-bodies in the reversible masking and silencing of mRNAs at the synapse.
“…NMDAR stimulation globally inhibits dendritic protein synthesis with consequences for translation specificity (reviewed in Thomas et al, 2014). Here, we show that the translational silencing upon exposure to NMDA is linked to the formation of synaptic XRN1-positive bodies, which are novel post-synaptic bodies that contain XRN1 and apparently lack decapping activity and that we termed SX-bodies.…”
Section: Discussionmentioning
confidence: 84%
“…RNA molecules might contribute to the stability of RNP liquid droplets by serving as a platform for multiple binding, and we found that RNA breakdown affects SX-body integrity. Additional cohesive forces that might help the condensation of RNP liquid droplets depend on homotypic and heterotypic protein-protein interaction mediated largely by low complexity regions (LCRs) Kato et al, 2012;Brangwynne, 2013;Jonas and Izaurralde, 2013;Thomas et al, 2014). The XRN1 C-terminus displays several LCRs, some of them rich in proline, and we speculate that these LCRs are likely to play a role in SX-body aggregation (Fig.…”
Section: What Is the Nature Of The Sx-bodies?mentioning
Repression of mRNA translation is linked to the formation of specific cytosolic foci such as stress granules and processing bodies, which store or degrade mRNAs. In neurons, synaptic activity regulates translation at the post-synapse and this is important for plasticity. Nmethyl-D-aspartate (NMDA) receptor stimulation downregulates translation, and we speculate that this is linked to the formation of unknown mRNA-silencing foci. Here, we show that the 59-39 exoribonuclease XRN1 forms discrete clusters associated with the post-synapse that are different from processing bodies or stress granules, and we named them synaptic XRN1 bodies (SX-bodies). Using primary neurons, we found that the SX-bodies respond to synapse stimulation and that their formation correlates inversely with the local translation rate. SX-bodies increase in size and number upon NMDA stimulation, and metabotropic glutamate receptor activation provokes SX-body dissolution, along with increased translation. The response is specific and the previously described Smaug1 foci and FMRP granules show a different response. Finally, XRN1 knockdown impairs the translational repression triggered by NMDA. Collectively, these observations support a role for the SX-bodies in the reversible masking and silencing of mRNAs at the synapse.
“…A central regulator for structural plasticity is the enzyme glycogen synthase kinase 3β (GSK3β), which is a target of many psychotropic drugs [8]: Long-term potentiation, which is a functional correlate of synaptic plasticity, leads to inhibition of GSK3β [56, 146], which in turn increases structural plasticity by destabilization and increased turnover of dendritic spines [140]. Furthermore, a host of cytoskeletal proteins [178], as well as local protein translation [197], is required for the proper maintenance and turnover of dendritic spines.Fig. 1Dendritic spines are remodeled in enriched environment.…”
Synaptic failure is an immediate cause of cognitive decline and memory dysfunction in Alzheimer’s disease. Dendritic spines are specialized structures on neuronal processes, on which excitatory synaptic contacts take place and the loss of dendritic spines directly correlates with the loss of synaptic function. Dendritic spines are readily accessible for both in vitro and in vivo experiments and have, therefore, been studied in great detail in Alzheimer’s disease mouse models. To date, a large number of different mechanisms have been proposed to cause dendritic spine dysfunction and loss in Alzheimer’s disease. For instance, amyloid beta fibrils, diffusible oligomers or the intracellular accumulation of amyloid beta have been found to alter the function and structure of dendritic spines by distinct mechanisms. Furthermore, tau hyperphosphorylation and microglia activation, which are thought to be consequences of amyloidosis in Alzheimer’s disease, may also contribute to spine loss. Lastly, genetic and therapeutic interventions employed to model the disease and elucidate its pathogenetic mechanisms in experimental animals may cause alterations of dendritic spines on their own. However, to date none of these mechanisms have been translated into successful therapeutic approaches for the human disease. Here, we critically review the most intensely studied mechanisms of spine loss in Alzheimer’s disease as well as the possible pitfalls inherent in the animal models of such a complex neurodegenerative disorder.
“…These higher-order assemblies of mRNAs and proteins are thought as units for mRNA transport and translational regulation. The molecular mechanisms for mRNA repression during granule movement are partially known and involve several RNA-binding proteins (RBPs; Thomas et al, 2014). Dendritic RNA granules may contain stalled polysomes, thus allowing a fast resuming of protein production (Graber et al, 2013).…”
The transcriptome at the synapse consists of thousands of messengers encoding several cellular functions, including a significant number of receptors and ion channels and associated proteins. The concerted translational regulation of all these molecules contributes to the dynamic control of synaptic strength. Cumulative evidence supports that dendritic RNA granules and mRNA-silencing foci play an important role in translational regulation. Several relevant RBPs – FMRP; FUS/TLS; TDP-43; Staufen; Smaug; Pumilio; CPEB; HuD; ZBP1; and DDX6 among others – form granules that contain dormant mRNAs repressed by multiple pathways. Recent reports indicate that dendritic granules may contain stalled polysomes, and furthermore, active translation may occur in association with RNA granules. Here, we discuss the molecules and pathways involved in this continuum of RNA granules that contain masked mRNAs, mRNAs trapped in inactive polysomes or mRNAs engaged in translation.
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