Synaptic control of mRNA translation by reversible assembly of XRN1 bodies

Luchelli, Luciana; Thomas, María Gabriela; Boccaccio, Graciela Lidia

doi:10.1242/jcs.163295

Cited by 26 publications

(42 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The kinetics of protein synthesis was inversely correlated with the kinetics of ATP consumption. Group I mGluR have been widely reported to activate protein synthesis [19,20,72] across various brain regions [73–75]. Our results indicate that mGluR mediated translation activation produced a rapid reduction in the synaptic-dendritic ATP level.…”

Section: Discussionsupporting

confidence: 50%

“…Our results demonstrate mGluR dependent translation activation consumes significant amount of ATP and shares distinct kinetic features to that of NMDAR. Gp I mGluRs have been widely reported to activate protein synthesis (Weiler et al 2004)(Luchelli, Thomas, and Boccaccio 2015) and induce or facilitate long-term depression in excitatory synapses (Huber, Kayser, and Bear 2000) across various brain regions [reviewed in (Bellone, Lüscher, and Mameli 2008)(Schulte 2010)(Jörntell and Hansel 2006)]. Our results indicate that, mGluR mediated translation activation impact global, dendritic and synaptic energy level immediately.…”

Section: Discussionmentioning

confidence: 55%

“…Group I metabotropic glutamate receptors (mGluRs referred hereafter) and NMDARs are widely implicated to facilitate or induce various forms of synaptic plasticity across different brain regions (Hunt and Castillo 2012)(Malenka 2012). While mGluRs are known to activate translation rapidly (Huber, Kayser, and Bear 2000)(Luchelli, Thomas, and Boccaccio 2015), NMDAR stimulation causes translation inhibition at an immediate time scale (Scheetz, Nairn, and Constantine-paton 2000). Considering the distinct nature of their downstream regulation, it would therefore be interesting to understand the impact of mGluR and NMDAR activation on cellular energetics.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Distinct Regulation of Bioenergetics and Translation by Group I mGluR and NMDAR

Dastidar

Sharma

Chakraborty

et al. 2019

Preprint

View full text Add to dashboard Cite

21Neuronal activity is responsible for disproportionally large consumption of energy by 22 the brain. However, little is known about the processes within neurons responsible for 23 such abundant ATP outlay. Here we provide evidence that major fraction of ATP 24 consumed on glutamate stimulation is due to activation of global de-novo protein 25 synthesis mediated by group I mGluRs in cultured cortical neurons. We found mGluR 26 and NMDAR stimulation impacts translation with distinct kinetics; while mGluR lead to 27 rapid and sustained translation activation as measured by eEF2 phosphorylation and 28 metabolic labeling, NMDAR stimulation induced a robust translation inhibition. Our 29 observations established an inverse correlation between the kinetics of translation and 30 change in ATP level for both receptors. We observed an immediate mGluR mediated 31 reduction in neuronal ATP level while NMDA lead to a delayed (≥15 mins) protein 32 synthesis dependent ATP expenditure demonstrating a possibility for NMDAR dependent 33 delayed translation activation. Interestingly, we identified that AMP activated protein 34 kinase (AMPK) has a central role in regulating downstream effects of both mGluR and 35 NMDAR. AMPK activity was reduced on mGluR stimulation even under low ATP levels 36 while there was a rapid increase in AMPK activity on NMDAR stimulation. Perturbing 37 AMPK function prior to either stimulation led to a complete loss of stimulation specific 38 effects on eEF2 phosphorylation and global translation. Our observation therefore 39 established a pivotal role for AMPK-eEF2 signaling axis on receptor specific regulation 40 of global translation.41 42 109 dependent reduction was absent in presence of protein synthesis inhibitors anisomycin 110 (25μM) or cycloheximide (100μg/ml) (Figure 1B) while drugs themselves had no 111 significnat impact on the ATP/(ATP+ADP) ratio. These observations suggest a large 112 increase in protein synthesis on stimulation, responsible for consuming signifcant 113 fraction of neuronal ATP. The identical effects of both anisomycin and cycloheximide 114 negates the possibility of these observations due to non-specific effects of these drugs. 115 Further, to understand the contributions from individual glutamate receptors, we 116 repeated glutamate stimulation inhibiting either ionotropic NMDA and AMPA receptors 117 with a cocktail of D-AP5 (25μM) + CNQX (40μM) (referred to as inotropic glutamate 118 receptor (iGluR) blocker cocktail hereafter) or inhibiting mGluRs with MPEP (10μM). Co-119 stimulation with iGluR blocker cocktail led to significant reduction in ATP/(ATP+ADP) 120 ratio similar to glutamate alone while stimulation along with MPEP abolished the 121 glutamate mediated reduction significantly (Figure 1C). These results therefore, 122 indicate that the observed reduction in ATP on glutamate stimulation is majorly due to 123 mGluR activity with minimal contributions from the iGluRs. Furthermore, Stimulation 124 in presence iGluR blocker cocktail along with protein synthesis inhib...

show abstract

Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Distinct Regulation of Bioenergetics and Translation by Group I mGluR and NMDAR

Dastidar

Sharma

Chakraborty

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The motor proteins facilitate traffic along MTs or actin filaments (Gumy et al, 2013). In addition to motor proteins, mRNP-granules also include ribosome particles, translation factors and signaling proteins (M€ uller-McNicoll & Neugebauer, 2013), and mRNA degradation factors (Luchelli, Tomas, & Boccaccio, 2015). P-bodies also include miRNAs in a RNA-induced silencing complex (RISC) and may represent sites of translationally repressed mRNP storage (Liu, Valencia-Sanchez, Hannon, & Parker, 2005).…”

Section: Long-lived Mrnas and Rna-binding Proteinsmentioning

confidence: 99%

RNA‐binding proteins of the NXF (nuclear export factor) family and their connection with the cytoskeleton

et al. 2017

View full text Add to dashboard Cite

The mutual relationship between mRNA and the cytoskeleton can be seen from two points of view. On the one hand, the cytoskeleton is necessary for mRNA trafficking and anchoring to subcellular domains. On the other hand, cytoskeletal growth and rearrangement require the translation of mRNAs that are connected to the cytoskeleton. b-actin mRNA localization may influence dynamic changes in the actin cytoskeleton. In the cytoplasm, long-lived mRNAs exist in the form of RNP (ribonucleoprotein) complexes, where they interact with RNA-binding proteins, including NXF (Nuclear eXport Factor). Dm NXF1 is an evolutionarily conserved protein in Drosophila melanogaster that has orthologs in different animals. The universal function of nxf1 genes is the nuclear export of different mRNAs in various organisms. In this mini-review, we briefly discuss the evidence demonstrating that Dm NXF1 fulfils not only universal but also specialized cytoplasmic functions. This protein is detected not only in the nucleus but also in the cytoplasm. It is a component of neuronal granules. Dm NXF1 marks nuclear division spindles during early embryogenesis and the dense body on one side of the elongated spermatid nuclei. The characteristic features of sbr mutants (sbr 10 and sbr 5 ) are impairment of chromosome segregation and spindle formation anomalies during female meiosis. sbr 12 mutant sterile males with immobile spermatozoa exhibit disturbances in the axoneme, mitochondrial derivatives and cytokinesis. These data allow us to propose that the Dm NXF1 proteins transport certain mRNAs in neurites and interact with localized mRNAs that are necessary for dynamic changes of the cytoskeleton. K E Y W O R D Snxf, long-lived mRNA, RNA-binding protein, spermatogenesis, localized translation | RNAS EXIST FOR THE CYTOSKELETON, A N D TH E C Y T O S K E L E T O N EX IS T S F O R RN A SThe cytoskeleton is a dynamic cellular structure. It supports the cel-

show abstract

“…One particular foci that forms with NMDAR stimulation is the synaptic XRN1 bodies (SX-bodies). While XRN1 is an RBP that is best known for its role in mRNA decay, SX-bodies lack decapping activity and therefore serve to sequester mRNAs (Luchelli et al, 2015). Since these bodies increase upon NMDAR stimulation, it is interesting to ask, what happens to SX-bodies with NMDAR antagonism?…”

Section: Perspectives and Open Questionsmentioning

confidence: 99%

Pushing the threshold: How NMDAR antagonists induce homeostasis through protein synthesis to remedy depression

et al. 2016

View full text Add to dashboard Cite

Healthy neurons have an optimal operating range, coded globally by the frequency of action potentials or locally by calcium. The maintenance of this range is governed by homeostatic plasticity. Here, we discuss how new approaches to treat depression alter synaptic activity. These approaches induce the neuron to recruit homeostatic mechanisms to relieve depression. Homeostasis generally implies that the direction of activity necessary to restore the neuron’s critical operating range is opposite in direction to its current activity pattern. Unconventional antidepressant therapies deep brain stimulation and NMDAR antagonists alter the neuron’s “depressed” state by pushing the neuron’s current activity in the same direction but to the extreme edge. These therapies rally the intrinsic drive of neurons in the opposite direction, thereby allowing the cell to return to baseline activity, form new synapses, and restore proper communication. In this review, we discuss seminal studies on protein synthesis dependent homeostatic plasticity and their contribution to our understanding of molecular mechanisms underlying the effectiveness of NMDAR antagonists as rapid antidepressants. Rapid antidepressant efficacy is likely to require a cascade of mRNA translational regulation. Emerging evidence suggests that changes in synaptic strength or intrinsic excitability converge on the same protein synthesis pathways, relieving depressive symptoms. Thus, we address the question: Are there multiple homeostatic mechanisms that induce the neuron and neuronal circuits to self-correct to regulate mood in vivo? Targeting alternative ways to induce homeostatic protein synthesis may provide, faster, safer, and longer lasting antidepressants.

show abstract

Synaptic control of mRNA translation by reversible assembly of XRN1 bodies

Cited by 26 publications

References 84 publications

Distinct Regulation of Bioenergetics and Translation by Group I mGluR and NMDAR

Distinct Regulation of Bioenergetics and Translation by Group I mGluR and NMDAR

RNA‐binding proteins of the NXF (nuclear export factor) family and their connection with the cytoskeleton

Pushing the threshold: How NMDAR antagonists induce homeostasis through protein synthesis to remedy depression

Contact Info

Product

Resources

About