Exaggerated translation causes synaptic and behavioural aberrations associated with autism

Santini, Emanuela; Huynh, Thu N.; MacAskill, Andrew F.; Carter, Adam G.; Pierre, Philippe; Ruggero, Davide; Kaphzan, Hanoch; Klann, Eric

doi:10.1038/nature11782

Cited by 319 publications

(373 citation statements)

References 37 publications

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“…Moreover, it highlights an important mechanistic difference between mGluR-LTD and L-LTP; although both types of plasticity are translation-dependent, the latter shows a stricter requirement for translation of newly initiated mRNAs. Our results are consistent with recent studies using the initiation inhibitor 4EGI-1, which report a block in L-LTP (28) but not striatal mGluR-dependent LTD (28,29).…”

Section: Discussionsupporting

confidence: 83%

Reactivation of stalled polyribosomes in synaptic plasticity

Graber

Hébert-Seropian

Khoutorsky

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

156

147

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Some forms of synaptic plasticity require rapid, local activation of protein synthesis. Although this is thought to reflect recruitment of mRNAs to free ribosomes, this would limit the speed and magnitude of translational activation. Here we provide compelling in situ evidence supporting an alternative model in which synaptic mRNAs are transported as stably paused polyribosomes. Remarkably, we show that metabotropic glutamate receptor activation allows the synthesis of proteins that lead to a functional long-term depression phenotype even when translation initiation has been greatly reduced. Thus, neurons evolved a unique mechanism to swiftly translate synaptic mRNAs into functional protein upon synaptic signaling using stalled polyribosomes to bypass the ratelimiting step of translation initiation. Because dysregulated plasticity is implicated in neurodevelopmental and psychiatric disorders such as fragile X syndrome, this work uncovers a unique translational target for therapies.M ost studies of translational control focus on initiation, the process where mRNAs recruit ribosomes and catalyze the first step of translation (1). This highly regulated and normally rate-limiting step of translation is followed by elongation and termination, resulting in completed proteins. Although multiple ribosomes on a given mRNA (a polyribosome) imply active peptide synthesis, we and others identified neuronal RNA granulesmotile aggregates of nontranslating ribosomes (2, 3). These electron-dense bodies contain single copies of synaptic mRNAs that are translationally silenced during their transport from soma to synapse (1, 4).Many models assume that neuronally transported mRNAs are translationally paused before completion of the initiation step of translation during transport. An appropriate synaptic signal would then activate translation (initiation/elongation/termination) of the granule mRNA. However, it is not clear how many free ribosomal subunits are present at synapses to support translation initiation. Further, at a typical translation elongation rate of six amino acids per s (5, 6), synthesis of larger synaptic proteins (e.g., microtubule-associated protein 1b; MAP1b) would take over 5 min even if initiation were immediate. These two factors constrain the speed and magnitude of synaptic translation and, thus, plasticity. As some forms of synaptic plasticity require rapid (<10 min) and localized activation of protein synthesis, an alternative model is wanting (7-9).We have previously proposed the concept of a neuronal RNA granule as a stalled polyribosome (10, 11). Ribosomal stalling has been shown to occur in lysates from a mouse neuroblastoma cell line and in an in vitro rabbit reticulocyte lysate translation assay programmed with brain homogenate (12). Whether neuronal ribosome stalling occurs in vivo is uncertain. We hypothesized that neuronal RNA granules contain paused ribosomes with incomplete proteins initiated in the soma before their packaging and transport to dendrites, where translation can be rapidly and loca...

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Section: Discussionsupporting

confidence: 83%

Reactivation of stalled polyribosomes in synaptic plasticity

Graber

Hébert-Seropian

Khoutorsky

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

156

147

View full text Add to dashboard Cite

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“…For example, excessive protein synthesis that occurs in Drosophila Fragile X mutants blocks long-term memory (Bolduc et al, 2008). Also, increasing the levels of eIF4E in mice results in exaggerated cap-dependent translation and causes synaptic pathology and autism-like behavior (Gkogkas et al, 2013;Santini et al, 2013). Thus, ubiquitin proteasome-mediated protein degradation is likely to be critical for physiological regulation of translation in the nervous system and therefore perturbation of proteolytic regulation of translation might lead to neuronal pathology.…”

Section: Possible Roles Of Protein Degradation In Regulating Translatmentioning

confidence: 99%

Proteasome Modulates Positive and Negative Translational Regulators in Long-Term Synaptic Plasticity

et al. 2014

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Proteolysis by the ubiquitin-proteasome pathway appears to have a complex role in synaptic plasticity, but its various functions remain to be elucidated. Using late phase long-term potentiation (L-LTP) in the hippocampus of the mouse as a model for long-term synaptic plasticity, we previously showed that inhibition of the proteasome enhances induction but blocks maintenance of L-LTP. In this study, we investigated the possible mechanisms by which proteasome inhibition has opposite effects on L-LTP induction and maintenance. Our results show that inhibiting phosphatidyl inositol-3 kinase or blocking the interaction between eukaryotic initiation factors 4E (eIF4E) and 4G (eIF4G) reduces the enhancement of L-LTP induction brought about by proteasome inhibition suggesting interplay between proteolysis and the signaling pathway mediated by mammalian target of rapamycin (mTOR). Also, proteasome inhibition leads to accumulation of translational activators in the mTOR pathway such as eIF4E and eukaryotic elongation factor 1A (eEF1A) early during L-LTP causing increased induction. Furthermore, inhibition of the proteasome causes a buildup of translational repressors, such as polyadenylate-binding protein interacting protein 2 (Paip2) and eukaryotic initiation factor 4E-binding protein 2 (4E-BP2), during late stages of L-LTP contributing to the blockade of L-LTP maintenance. Thus, the proteasome plays a critical role in regulating protein synthesis during L-LTP by tightly controlling translation. Our results provide novel mechanistic insights into the interplay between protein degradation and protein synthesis in long-term synaptic plasticity.

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“…[17][18][19] Other studies utilizing 4EGI-1 as an inhibitor of cap-dependent translation have significantly contributed to our understanding of the role of eIF4F complex in autism spectrum disorders, memory formation and consolidation and viral infection. [20][21][22][23] In this study, we investigated the effects of 4EGI-1 on PI3K/ Akt/mTORC1 signaling due to its critical role in the regulation of cap-dependent translation initiation. We found that 4EGI-1 inhibits mTORC1 signaling and that this inhibitory role was independent from the inhibition of cap-dependent translation initiation.…”

Section: Introductionmentioning

confidence: 99%

The synergistic inhibition of breast cancer proliferation by combined treatment with 4EGI-1 and MK2206

et al. 2015

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Abbreviations: eIF4E, eukaryotic translation initiation factor 4E; 4EBP1, eIF4E-binding protein 1; p70S6K, ribosomal p70 S6 kinase; mTORC1, mammalian target of rapamycin complex 1; mTORC2 mammalian target of rapamycin complex 2; PI3K, phosphatidylinositol 3-kinase; ER stress, endoplasmic reticulum stress.Cap-dependent translation is a potential cancer-related target (oncotarget) due to its critical role in cancer initiation and progression. 4EGI-1, an inhibitor of eIF4E/eIF4G interaction, was discovered by screening chemical libraries of small molecules. 4EGI-1 inhibits cap-dependent translation initiation by impairing the assembly of the eIF4E/eIF4G complex, and therefore is a potential anti-cancer agent. Here, we report that 4EGI-1 also inhibits mTORC1 signaling independent of its inhibitory role on cap-dependent translation initiation. The inhibition of mTORC1 signaling by 4EGI-1 activates Akt due to both abrogation of the negative feedback loops from mTORC1 to PI3K and activation of mTORC2. We further validated that mTORC2 activity is required for 4EGI-1-mediated Akt activation. The activated Akt counteracted the anticancer effects of 4EGI-1. In support of this model, inhibition of Akt potentiates the antitumor activity of 4EGI-1 both in vitro and in a xenograft mouse model in vivo. Our results suggest that a combination of 4EGI-1and Akt inhibitor is a rational approach for the treatment of cancer.

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Exaggerated translation causes synaptic and behavioural aberrations associated with autism

Cited by 319 publications

References 37 publications

Reactivation of stalled polyribosomes in synaptic plasticity

Reactivation of stalled polyribosomes in synaptic plasticity

Proteasome Modulates Positive and Negative Translational Regulators in Long-Term Synaptic Plasticity

The synergistic inhibition of breast cancer proliferation by combined treatment with 4EGI-1 and MK2206

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